Methods involving neutrophil elastase inhibitor alvelestat for treating coronavirus infection

ABSTRACT

The invention relates to treatments for coronavirus infections by administering a neutrophil elastase inhibitor, such as alvelestat.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of: US provisional application U.S. 62/706,195, filed 4 Aug. 2020; United Kingdom patent application number 2005519.0, filed 16 Apr. 2020; and United Kingdom patent application number 2005520.8, filed 16 Apr. 2020. The contents of these applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to new methods for treating a coronavirus infection (e.g. SARS-CoV-02/COVID-19), symptoms and complications thereof, and conditions associated with such an infection, comprising administering a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

BACKGROUND TO THE INVENTION

Infection with the SARS-CoV-2 virus has led to the coronavirus disease 2019 (COVID-19) pandemic, affecting global health and economies on an unprecedented scale. The spectrum of illness ranges from asymptomatic to critical, with mild symptoms in ˜80% of cases. However, severe disease is characterized by dyspnea, hypoxemia, and respiratory failure with acute respiratory distress syndrome, (ARDS), shock, disrupted coagulation with thromboses and/or excessive bleeding, and multi-organ failure. As of Jun. 10, 2020, the World Health Organization reported that there are over 7.2 million cases of COVID-19 worldwide, accounting for nearly 413,000 deaths (World Health Organization COVID-19 Situation Report 142, June 2020). While the use of stay-at-home orders, social distancing, and deployment of limited business models have resulted in a “flattening of the curve”, the number of new cases and deaths continue to rise and there are limited therapeutic options. Antiviral medications have shown the most promise as therapies for SARS-COV2 infection ([1], [2]). Other strategies have included targeting host inflammatory pathways or repurposing existing medications, although these have not all been successful in early trials ([3], [4], [5]). Preliminary results with dexamethasone in reducing mortality in severe cases supports the potential of immune modulators ([19]).

The clinical course of COVID-19 is characterised by initial symptoms typical of viral infection. In some individuals, this is followed several days later by rapid deterioration, concurrent with the onset of the immune response. An acute innate inflammatory response is typical, with elevated pro-inflammatory cytokines, marked elevation of acute phase reactants and cytokine storm. Available therapies consist of organ support, anti-coagulation to reduce risk of venous and arterial thrombosis, and as needed treatment of infection and sepsis. Repurposed existing immunomodulating therapies are being progressed through global ‘platform’ trials, including for anti-IL6, anti-IL1, dexamethasone and hydroxychloroquine, with results emerging. None are specifically targeting neutrophil-driven pathogenic mechanisms.

There is therefore a need for new therapies for treating a coronavirus infection (e.g. SARS-CoV-02/COVID-19) and/or preventing progression of a coronavirus disease (e.g. SARS-CoV-02/COVID-19).

SUMMARY OF THE INVENTION

The present invention provides inhibitors of neutrophil elastase (NE), in particular alvelestat, for treating a coronavirus infection and/or preventing progression of a coronavirus disease. Preferably the coronavirus is SARS-CoV-2 (COVID-19).

Without wishing to be bound by theory, alvelestat is expected to be therapeutically useful due to its ability to inhibit neutrophil elastase. As discussed in Example 2, neutrophil elastase is essential to neutrophil extracellular traps (NETs) formation ([6]). NETs are networks of extracellular DNA fibers, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), released from neutrophils and involved physiologically in capturing bacteria. The process of NETs generation is called NETosis. If uncontrolled, NETs are cytotoxic to endothelial and epithelial cells; acting as Damage Associated Molecular Pattern Molecules (DAMPs), promoting cytokine release and thromboses ([7]). The physiological inhibitor of NE is Alpha-1 antitrypsin (AAT), but studies in COVID-19 have shown this to be overwhelmed ([8]) and have shown that neutrophils and NETs are a central feature of COVID-19 pathogenesis. Treatment with alvelestat according to the present invention may therefore impact the disease progression of coronavirus infections, in particular COVID-19, through inhibition of neutrophil elastase, decreasing levels of NETs, and disruption of NETosis.

Neutrophil elastase has also been implicated in increasing the infectivity of COVID-19, and therefore, the inhibition of neutrophil elastase could reduce viral replication ([20]). Without wishing to be bound by theory, the administration of alvelestat or a pharmaceutically acceptable salt thereof may therefore prevent replication of a coronavirus in a subject thereby treating the coronavirus infection and/or preventing progression of coronavirus disease. This may occur via a pathway that involves the inhibition of neutrophil elastase.

Thus the present invention generally provides a method for treating a coronavirus infection and/or preventing progression of a coronavirus disease, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for preventing the progression of a coronavirus disease, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating a coronavirus disease, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing a symptom or complication of a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for reducing viral replication of a coronavirus, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing tissue injury associated with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing acute lung injury (ALI) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing acute respiratory distress syndrome (ARDS) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing inflammation in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing neutrophilia in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing coagulopathy (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing antiphospholipid syndrome (APS) (also referred to as antiphospholipid antibody syndrome (APLS)) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing organ failure in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof. One or more organs (e.g. the lungs, kidneys, heart) may be affected. For example, the organ failure may be multi-organ failure.

The present invention also generally provides a method for treating or preventing respiratory failure in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing renal failure in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing cardiac failure (e.g. myocarditis) in a subject with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing a condition associated with a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing coronavirus induced coagulopathy complications (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding), comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing coronavirus induced respiratory complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing coronavirus induced cardiac complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present invention also generally provides a method for treating or preventing coronavirus induced renal complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

Preferably, the coronavirus is SARS-COV, most preferably COVID-19. Preferably the neutrophil elastase inhibitor is alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.

DETAILED DESCRIPTION

The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the present disclosure. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Throughout this specification and in the claims that follow, the following terms are defined with the following meanings, unless explicitly stated otherwise.

Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, i.e. as “including, but not limited to”.

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

As used herein, the term “or” is generally employed in the sense as including “and/or” unless the context of the usage clearly indicates otherwise.

Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

As used herein, the term “about” means the recited value ±10% of the recited value.

As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results. For purposes of the present invention, beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom associated with a disease or condition. “Treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.

As used herein, “prevention” or “preventing” refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop. Thus, “prevention” may relate to administration of a therapy (e.g., administration of a therapeutic substance) to a subject before signs of the disease are detectable in the subject. The subject may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder.

As used herein, “preventing progression” refers to a regimen that protects against the further development (e.g. worsening) of the disease or disorder in a subject.

As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the particular compound, and characteristics of the subject to be treated, such as age, weight, etc. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and a one or more pharmaceutically acceptable solvent molecules, for example, ethanol or water. The term “hydrate” is employed when the solvent is water and for the avoidance of any doubt, the term “hydrate” is encompassed by the term “solvate”.

The term “pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. For example, where a compound contains a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like. Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts. For a review of suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH, 2011). “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms etc. which are suitable for pharmaceutical use.

The term “subject” preferably refers to a human.

All documents referenced herein are each incorporated by reference in their entirety for all purposes.

Alvelestat

The preferred neutrophil elastase inhibitor used in the invention is alvelestat.

Alvelestat is a potent, orally bioavailable neutrophil elastase inhibitor described in WO 2005/026123 A1 (Example 94, page 85) and [11], which are incorporated herein by reference in their entirety. Alvelestat has the chemical name N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, and the following chemical structure:

Alvelestat has also been referred to as AZD9668 and MPH996.

Alvelestat may be used in the invention in any pharmaceutically acceptable form, for example any free base form, salt form, and/or solvate form. Alvelestat or a pharmaceutically acceptable salt and/or solvate thereof may be present in any pharmaceutically acceptable physical form, suitably a solid form.

Certain salts of alvelestat are described in WO 2010/094964 A1, which is incorporated herein by reference in its entirety. Described salts of alvelestat include the tosylate, p-xylene-2-sulfonate, chloride, mesylate, esylate, 1,5-naphthalenedisulfonate and sulfate.

Preferably, alvelestat free base or alvelestat tosylate is used in the methods of the invention, more preferably alvelestat tosylate.

Alvelestat may also be used in any of the methods of the invention in a pharmaceutically acceptable prodrug form.

Neutrophil Elastase Inhibitors

Neutrophil elastase (NE) is an enzyme that attacks and progressively damages lung tissue. Compounds that inhibit NE are reviewed in [9] and are known from various publications including WO2017207430, WO2017102674, WO2016050835, WO2016050835, WO2016016368, WO2016016366, WO2016016365, WO2016016364, WO2016016363, WO2015124563, WO2016020070, WO2015091281, WO2014135414, WO2014122160, WO2015096873, WO2015096872, WO2014029832, WO2014029831, WO2014029830, WO2014009425, WO2013084199, WO2013037809, WO2011103774, WO2011110858, WO2011110859, WO2011110852, WO2011039528, WO2010034996, WO2009061271, WO2009058076, WO2009060206, WO2007137080, WO2007137080, WO2007140117, WO2008036379, WO2008036379, WO9962538, WO9962538, WO9962514, WO9739028, WO9616080, WO9533763, WO9533762, WO9527055, WO9311760, WO9220357, WO9215605, WO9215605, WO03058237, WO03031574, WO03031574, WO2008030158, WO2007129963, WO2007129962, WO2006098684, WO2005026124, WO2005026123, WO2005021509, WO2005021512, WO2004043924, WO2009060158, WO2009037413, WO2009013444, WO2007129060, WO2007107706, WO2007107706, WO2006136857, WO2006082412, WO2006082412, WO9623812, WO9521855, WO9401455, WO9324519, WO9321214, WO9321210, WO9321213, WO9321209, WO9321212, WO2006070012, WO2005082863, WO2005082863, WO2005082864, WO9912933, WO9912933, WO9912931, WO9736903, WO2004020412, WO2008104752, WO2008097676, WO200809767, WO2008085608, each of which is incorporated by reference. Each of the neutrophil inhibitors described in these publications may be used in the methods of the invention, and is referred to as if it were individually disclosed herein for use in the methods of the invention.

In addition to the preferred neutrophil elastase inhibitor alvelestat, other exemplary neutrophil elastase inhibitors that may be used in the present invention include sivelestat, ONO-5046-Na, depelestat, Prolastin, KRP-109, DX-890, pre-elafin, MNEI, BAY 85-8501, POL6014, a1-AT, sirtinol, ONO-6818 (2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-1-yl)-N-[(1R, 2R)-1-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-hydroxy-3-methylbutan-2-yl]acetamide), elastatinal, SSR 69071 (2-[[6-methoxy-4-(1-methylethyl)-1,1-dioxo-3-oxo-1,2-benzisothiazol-2(3H)-yl]methoxy]-9-[2-(1-piperidinyl)ethoxy]-4H-pyrido[1,2-a]pyrimidin-4-one), and M0398 (N-(methoxysuccinyl)-L-alanyl-L-alanyl-L-prolyl-L-valine chrolomethylketone); and their pharmaceutically acceptable salts and/or solvates.

The term neutrophil elastase inhibitor includes all pharmaceutically acceptable forms of the compounds, for example all pharmaceutically acceptable salt, solvate, isomer, and prodrug forms.

In certain embodiments, the neutrophil elastase inhibitor is a small molecule compound, i.e. has a molecular weight of less than about 900 daltons.

Preferably the neutrophil elastase inhibitors are inhibitors of human neutrophil elastase.

Although many embodiments of this invention relate to alvelestat, it should be understood that for each and every embodiment described herein referring to “alvelestat”, the invention also provides a corresponding embodiment involving the use of “a neutrophil elastase inhibitor”.

Treatments

The invention generally provides methods for treating a coronavirus infection and/or preventing progression of a coronavirus disease in a subject in need thereof comprising administering to the subject an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof. Accordingly, the present invention provides a method for treating a coronavirus infection and/or preventing progression of coronavirus disease, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

The present invention also provides a method for treating or preventing a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

In an embodiment, the present invention provides a method for treating or preventing a symptom of a coronavirus infection. In an embodiment, the present invention provides a method for treating or preventing a complication of a coronavirus infection. In an embodiment, the method for treating or preventing a symptom or a complication of a coronavirus infection is a method for ameliorating a symptom or a complication of a coronavirus infection. In an embodiment, the method for treating or preventing a symptom or a complication of a coronavirus infection is a method for preventing worsening of a symptom or a complication of a coronavirus infection. Preferably, the symptom or complication is a respiratory symptom or complication.

In an embodiment, the coronavirus infection is a viral respiratory disease.

A “coronavirus” is a group of related RNA viruses that can cause diseases in mammals and birds. In human subjects, these viruses can cause respiratory tract infections, other symptoms, and/or complications. Lethal varieties of coronaviruses can cause severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome coronavirus MERS, and COVID-19. The term “coronavirus” is used interchangeably with “virus” in this disclosure. The term “coronavirus” and “coronavirus infection” can be used interchangeably in this disclosure.

Severe acute respiratory syndrome coronavirus (SARS-CoV or SARSr-CoV) is a species of coronavirus that infects at least humans and bats. SARS-CoV is an enveloped positive-sense single-stranded RNA virus that enters its host cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. The terms “SARS-CoV-2” and “COVID-19” can be used interchangeably.

In preferred embodiments, the coronavirus infection is severe acute respiratory syndrome coronavirus (SARS-CoV). SARS-COV may be of any strain. In an embodiment, the SARS-CoV is SARS-CoV-1. In an embodiment, the SARS-CoV is SARS-CoV-2 (COVID-19).

In another embodiment, the coronavirus infection is Middle East respiratory syndrome coronavirus (MERS-CoV).

Accordingly, the present invention provides a method for treating SARS-CoV and/or preventing progression of SARS-CoV disease, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. In an embodiment, the present invention provides a method for treating or preventing COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

Accordingly, the present invention provides a method for treating a SARS-CoV infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. In an embodiment, the present invention provides a method for treating COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

In an embodiment, the method for treatment of the present invention comprises treating or preventing a symptom or complication attributable to a SARS-COV infection, such as COVID-19.

In an embodiment, the present invention provides a method for treating or preventing a disease or condition associated with a SARS-COV infection, such as COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

In an embodiment, the present invention provides a method for treating or preventing a symptom or complication associated with a SARS-COV infection, such as COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

In an embodiment, the present invention provides a method for treating a symptom of a coronavirus infection. In an embodiment, the present invention provides a method for preventing a symptom of a coronavirus infection.

The disease, condition, symptom, and complication may be caused by or be attributable to a coronavirus infection.

Acute respiratory distress syndrome (ARDS) is a type of respiratory failure which can be characterized by inflammation in the lungs. Symptoms can include at least one of shortness of breath, rapid breathing, and bluish skin coloration. Causes of ARDS may include at least one of a coronavirus infection, sepsis, pancreatitis, trauma, pneumonia, and aspiration. The underlying mechanism may involve diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs, surfactant dysfunction, activation of the immune system, and dysfunction of the body's regulation of blood clotting. ARDS may impair the lungs' ability to exchange oxygen and carbon dioxide. An adult diagnosis may be based on a PaO₂/FiO₂ ratio (ratio of partial pressure arterial oxygen and fraction of inspired oxygen) of less than 300 mm Hg, optionally despite a positive end-expiratory pressure (PEEP) of more than 5 cm H₂O.

Without wishing to be bound by theory, a coronavirus infection may cause ARDS via a pathway that involves neutrophils and neutrophil extracellular traps (NETs). It has been established that NETs increase in patients with ARDS ([10]).

Accordingly, the present invention provides a method for the treatment or prevention of ARDS. The present invention provides a method for the treatment or prevention of ARDS in a subject with a coronavirus infection (in particular COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of ARDS associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of ARDS arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. Acute lung injury (ALI) can be defined as a lung inflammation that develops in response to a pulmonary and/or generalized acute diseases. The clinical features of acute lung injury may vary from at least one of mild, self-limiting dyspnoea to rapidly progressive and fatal respiratory failure. Without wishing to be bound by theory, a coronavirus infection may cause ALI via a pathway that involves neutrophils and NETs.

The present invention provides a method for the treatment or prevention of ALI. The present invention provides a method for the treatment or prevention of ALI in a subject with a coronavirus infection (in particular COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of ALI associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of ALI arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. Systemic inflammatory response syndrome (SIRS) can be an exaggerated defense response of the body to a noxious stressor (e.g. at least one of infection, trauma, surgery, acute inflammation, ischemia, reperfusion, and malignancy) to localize and then eliminate the endogenous or exogenous source of the stressor. Without wishing to be bound by theory, a coronavirus infection may cause SIRS via a pathway that involves neutrophils and NETs.

The present invention provides a method for the treatment or prevention of SIRS. The present invention provides a method for the treatment or prevention of SIRS in a subject with a coronavirus infection (in particular COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of SIRS associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of SIRS arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

Pulmonary fibrosis (also referred to as fibrosing lung disease) is a condition in which the lungs become scarred over time. Symptoms can include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing.

Without wishing to be bound by theory, a coronavirus infection may cause pulmonary fibrosis, possibly via a pathway that involves neutrophils and neutrophil extracellular traps (NETs).

In an embodiment, the present invention provides a method comprising the treatment or prevention of pulmonary fibrosis. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is pulmonary fibrosis. In an embodiment, the present invention provides a method for treatment wherein the subject has pulmonary fibrosis and a coronavirus infection.

Pneumonia can be an inflammatory condition of the lung(s) which can affect the small air sacs known as alveoli. Symptoms can include at least one of productive or dry cough, chest pain, fever and difficulty breathing.

The present invention provides a method for the treatment or prevention of pneumonia. The present invention provides a method for the treatment or prevention of pneumonia in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of pneumonia associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of pneumonia arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. In some embodiments, the pneumonia is viral pneumonia.

Inflammation of the lung(s) can also be termed pneumonitis. Without wishing to be bound by theory, inflammation of the lung(s) can be a general symptom or complication from any disease or condition (e.g. ARDS, ALI, and/or pneumonia). Inflammation of the lung(s) can be aggravated by or caused by a coronavirus infection. Without wishing to be bound by theory, a coronavirus infection may cause inflammation of the lung(s) via a pathway that involves neutrophils and NETs.

The present invention provides a method for the treatment or prevention of inflammation of the lungs. The present invention provides a method for the treatment or prevention of inflammation of the lungs in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of inflammation of the lungs associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of inflammation of the lungs arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. Respiratory failure can result from inadequate gas exchange by the respiratory system, meaning that oxygen levels and/or carbon dioxide levels cannot be kept at normal levels. A drop in the oxygen carried in blood can be known as hypoxemia; a rise in carbon dioxide levels is called hypercapnia. Respiratory failure is classified as either Type 1 or Type 2, based on whether there is a high carbon dioxide level, and can be either acute or chronic. The definition of respiratory failure can include increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Without wishing to be bound by theory, a coronavirus infection may cause respiratory failure NETs.

The present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2). The present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2) in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2) associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of respiratory failure (e.g. Type 1 or Type 2) arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

Coagulopathy (which can also be termed as a bleeding disorder) can be a condition in which the blood's ability to coagulate (form clots) is impaired. Coagulopathy can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur spontaneously or following an injury or medical and dental procedures. Without wishing to be bound by theory, a coronavirus infection may cause coagulopathy via a pathway that involves neutrophils and NETs.

The present invention provides a method for the treatment or prevention of coagulopathy. The present invention provides a method for the treatment or prevention of coagulopathy in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of coagulopathy associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of coagulopathy arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

Coagulopathy includes thrombosis (such as arterial thrombosis, venous thrombosis, and microthrombosis), excessive bleeding, and disseminated intravascular coagulation. In some embodiments, coagulopathy is thrombosis, such as arterial thrombosis, venous thrombosis, and microthrombosis. In some embodiments, coagulopathy is arterial thrombosis. In some embodiments, coagulopathy is venous thrombosis. In some embodiments, coagulopathy is disseminated intravascular coagulation. In some embodiments, coagulopathy is excessive bleeding. In some embodiments, coagulopathy is thromboses and complications thereof. In some embodiments, coagulopathy is thromboses and excessive bleeding.

Antiphospholipid syndrome (APS or APLS) is an autoimmune disorder. APS can cause blood clots (thrombosis) in both arteries and veins. APS can occur when a subject's immune system produces antibodies that attack phospholipids. Without wishing to be bound by theory, a coronavirus infection may cause APS via a pathway that involves neutrophils and NETs.

The present invention provides a method for the treatment or prevention of APS. The present invention provides a method for the treatment or prevention of APS in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of APS associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of APS arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

Multi-organ failure can also be referred to as multiple organ dysfunction syndrome or multiple organ failure. Without wishing to be bound by theory, a coronavirus infection may cause multi-organ failure via a pathway that involves neutrophils and NETs.

The present invention provides a method for the treatment or prevention of multi-organ failure. The present invention provides a method for the treatment or prevention of multi-organ failure in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of multi-organ failure associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of multi-organ failure arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

The organs may be any organs, for example, the heart, lung or kidney. In some embodiments, the organ failure comprises renal failure. In some embodiments, the organ failure comprises heart failure.

Cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and/or certain drugs. Without wishing to be bound by theory, a coronavirus infection may cause CRS via a pathway that involves neutrophils and NETs.

The present invention provides a method comprising the treatment or prevention of CRS. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is CRS. In an embodiment, the present invention provides a method for treatment wherein the subject has CRS and a coronavirus infection.

A cytokine storm, also called cytokine storm syndrome (CSS) or hypercytokinemia, is a physiological reaction in humans and other animals in which the immune system may cause an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Without wishing to be bound by theory, a coronavirus infection may cause a cytokine storm via a pathway that involves neutrophils and neutrophil extracellular traps (NETs).

The present invention provides a method comprising the treatment or prevention of a cytokine storm. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is a cytokine storm. In an embodiment, the present invention provides a method for treatment wherein the subject has a cytokine storm and a coronavirus infection.

Dyspnea can also be termed “shortness of breath” or “air hunger”. Without wishing to be bound by theory, a coronavirus infection may cause dyspnea, possibly via a pathway that involves neutrophils and NETs.

The present invention provides a method comprising the treatment or prevention of a dyspnea. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is dyspnea. In an embodiment, the present invention provides a method for treatment wherein the subject has dyspnea and a coronavirus infection.

Shock can be a life-threatening condition that occurs when the body is not receiving enough blood flow. Lack of blood flow can mean that cells and organs do not get enough oxygen and nutrients to function properly. Organs can be damaged as a result. Without wishing to be bound by theory, a coronavirus infection may cause shock via a pathway that involves neutrophils and NETs.

The present invention provides a method comprising the treatment or prevention of a shock. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is shock. In an embodiment, the present invention provides a method for treatment wherein the subject has shock and a coronavirus infection.

Hypoxemia can refers to the low level of oxygen in blood, and the more general term hypoxia can refer to an abnormally low oxygen content in any tissue or organ, or the body as a whole. Hypoxemia can cause hypoxia (hypoxemic hypoxia), but hypoxia can also occur via other mechanisms. Without wishing to be bound by theory, a coronavirus infection may cause hypoxemia via a pathway that involves neutrophils and NETs.

The present invention provides a method comprising the treatment or prevention of hypoxemia. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is hypoxemia. In an embodiment, the present invention provides a method for treatment wherein the subject has hypoxemia and a coronavirus infection.

Neutrophilia (sometimes also called neutrophil leukocytosis or neutrocytosis) is leukocytosis of neutrophils, i.e. a high number of neutrophils in the blood. Leukocytosis is a condition in which the white cell (leukocyte count) is above the normal range in the blood, and can be a sign of an inflammatory response. Neutrophilia can be a sign of an inflammatory response, possibly due to a coronavirus infection. Without wishing to be bound by theory, a coronavirus infection may cause neutrophilia via a pathway that involves neutrophils and NETs.

The present invention provides a method comprising the treatment or prevention of neutrophilia. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is neutrophilia. In an embodiment, the present invention provides a method for treatment wherein the subject has neutrophilia and a coronavirus infection.

A neurological disorder or complication is any disorder or complication of the nervous system. The nervous system includes the peripheral nervous system (PNS) and the central nervous system (CNS). The PNS generally includes the nerves and ganglia outside the brain and spinal cord. Whereas the CNS generally includes the brain and spinal cord. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. There are reports of subjects with coronavirus, e.g. COVID-19, who also have neurological disorders or complications. The neurological complications may cause COVID-19 symptoms such as loss of taste and/or loss of smell. Without wishing to be bound by theory, a coronavirus infection may cause a neurological complication via a pathway that involves neutrophils and NETs. Moreover, without wishing to be bound by theory, the administration of alevelstat or a pharmaceutically acceptable salt thereof may prevent replication of a coronavirus in a subject thereby reducing neurological complications.

The present invention provides a method for the treatment or prevention of a neurological complication. The present invention provides a method for the treatment or prevention of a neurological complication in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of a neurological complication associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of a neurological complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

In some embodiments, the neurological complication is a complication of the PNS. In some embodiments, the neurological complication is a complication of the CNS.

In some embodiments, the neurological complication is encephalopathy. Encephalopathy can be any disorder or disease of the brain. Encephalopathy can include chronic degenerative conditions. Encephalopathy is not a single disease, but rather encephalopathy is a syndrome of overall brain dysfunction. Signs and/or symptoms of encephalopathy can include an altered mental state or delirium. Characteristic of the altered mental state is impairment of the cognition, attention, orientation, sleep-wake cycle and consciousness of a subject. An altered state of consciousness may range from failure of selective attention to drowsiness.

In some embodiments, the neurological complication is a loss of smell. In some embodiments, the neurological complication is anosmia. In some embodiments, the neurological complication is ageusia. In some embodiments, the neurological complication is a loss of taste.

Guillain-Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. GBS has also been linked to a coronavirus infection (e.g. a COVID-19 infection). GBS may be a potential neurological complication from a coronavirus infection. Without wishing to be bound by theory, a coronavirus infection may cause GBS via a pathway that involves neutrophils and neutrophil extracellular traps (NETs).

In an embodiment, the present invention provides a method comprising the treatment or prevention of GBS. In an embodiment, the present invention provides a method for treatment wherein the symptom or complication is GBS. In an embodiment, the present invention provides a method for treatment wherein the subject has GBS and a coronavirus infection.

Thrombosis can occur in veins (venous thrombosis) or in arteries (arterial thrombosis). Venous thrombosis can lead to congestion of the affected part of the body, while arterial thrombosis (and rarely severe venous thrombosis) can affect the blood supply and/or can lead to damage of the tissue supplied by that artery (e.g. ischemia and necrosis). A piece of either an arterial or a venous thrombus can break off as an embolus which can travel through the circulation and lodge somewhere else as an embolism. This type of embolism is known as a thromboembolism. Complications can arise when a venous thromboembolism (commonly called a VTE) lodges in the lung as a pulmonary embolism. An arterial embolus may travel further down the affected blood vessel where it can lodge as an embolism. Without wishing to be bound by theory, a coronavirus infection may cause thrombosis via a pathway that involves neutrophils and neutrophil extracellular traps (NETs).

Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout a subject, blocking small blood vessels. For example, DIC can involve microthrombi formation in blood vessels (e.g. veins, arteries and/or capillaries). A microthrombus can be a microscopic clump of fibrin, platelets, and red blood cells. Symptoms of DIC may include one or more of chest pain, shortness of breath, leg pain, problems speaking, and/or problems moving parts of the body. DIC may be accompanied by ARDS.

The present invention provides a method for the treatment or prevention of thrombosis. The present invention provides a method for the treatment or prevention of thrombosis in a subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of thrombosis associated with a coronavirus infection in a subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of thrombosis arising as a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. In some embodiments, the thrombosis is venous thrombosis. In some embodiments, the thrombosis is arterial thrombosis. In some embodiments, the thrombosis is VTE which cause a pulmonary embolism. In some embodiments, the thrombosis is microthrombosis.

Thrombosis in a subject can cause non-vessel thrombotic complications. For example, vascular catheter thrombosis, vasculopathy, and/or vascular catheter thrombosis. Therefore, the treatment or prevention of venous and/or arterial thrombosis can be the treatment or prevention of a complication of thrombosis. In some embodiments, the complication is vascular catheter thrombosis. In some embodiments, the complication is vasculopathy. In some embodiments, the complication is vascular catheter thrombosis.

In an embodiment, the present invention provides a method comprising the treatment or prevention of one or more conditions selected from the group consisting of: a disease with signs and/or symptoms similar to Kawasaki disease, acute respiratory distress syndrome (ARDS), ageusia, arrhythmias, ALI, ALI/ARDS accompanied by Disseminated intravascular coagulation (DIC), ALI/ARDS accompanied by Systemic Inflammatory Response Syndrome, alveolar-capillary damage, alveolitis, anosmia, APS, arterial thrombosis, blood clot, bronchiectasis, cardiac complications, cardiovascular complications, chest tightness, coagulopathy, coagulopathy and/or excessive bleeding, coagulopathy complications, coughing, coughing up sputum, cystic fibrosis, cytokine release syndrome, cytokine storm hyperinflammation, cytokine storm syndrome, DIC and/or excessive bleeding, Dyspnea, Encephalitis, Encephalopathy, excessive bleeding, fatigue, fever, Guillain-Barré syndrome, heart failure, heart inflammation, heart palpitations, hyperinflammation, hypoxemia, inflammation disorders, inflammation disorders in paediatric subjects, inflammation of the lungs, Kawasaki disease, loss of appetite, loss of smell, loss of taste, lung consolidation, microthrombosis, multi-organ failure, muscle ache, neurological complications, neurological disorders, neutrophilia, Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS), Pericarditis, Pleurisy, Pneumonia, pulmonary disease, pulmonary embolism, pulmonary fibrosis, pulmonary oedema, renal complications, renal failure, respiratory failure, seizure, septic shock, shock, shortness of breath, stroke, Systemic inflammatory response syndrome (SIRS), Thromboses, thromboses and/or excessive bleeding, thrombosis or thromboses including venous and arterial thrombosis, thrombotic complications, vascular catheter thrombosis, vasculitis, vasculopathy, venous thrombosis, and viral pneumonia.

In an embodiment, the present invention provides a method comprising the treatment of a symptom or complication of a coronavirus infection selected from the group consisting of: a disease with signs and/or symptoms similar to Kawasaki disease, acute respiratory distress syndrome (ARDS), ageusia, arrhythmias, ALI, ALI/ARDS accompanied by Disseminated intravascular coagulation (DIC), ALI/ARDS accompanied by Systemic Inflammatory Response Syndrome, alveolar-capillary damage, alveolitis, anosmia, APS, arterial thrombosis, blood clot, bronchiectasis, cardiac complications, cardiovascular complications, chest tightness, coagulopathy, coagulopathy and/or excessive bleeding, coagulopathy complications, coughing, coughing up sputum, cystic fibrosis, cytokine release syndrome, cytokine storm hyperinflammation, cytokine storm syndrome, DIC and/or excessive bleeding, Dyspnea, Encephalitis, Encephalopathy, excessive bleeding, fatigue, fever, Guillain-Barré syndrome, heart failure, heart inflammation, heart palpitations, hyperinflammation, hypoxemia, inflammation disorders, inflammation disorders in paediatric subjects, inflammation of the lungs, Kawasaki disease, loss of appetite, loss of smell, loss of taste, lung consolidation, microthrombosis, multi-organ failure, muscle ache, neurological complications, neurological disorders, neutrophilia, Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS), Pericarditis, Pleurisy, Pneumonia, pulmonary disease, pulmonary embolism, pulmonary fibrosis, pulmonary oedema, renal complications, renal failure, respiratory failure, seizure, septic shock, shock, shortness of breath, stroke, Systemic inflammatory response syndrome (SIRS), Thromboses, thromboses and/or excessive bleeding, thrombosis or thromboses including venous and arterial thrombosis, thrombotic complications, vascular catheter thrombosis, vasculitis, vasculopathy, venous thrombosis, and viral pneumonia.

in an embodiment, the present invention provides a method for treating or preventing a condition in a subject with a coronavirus infection, in particular COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. In an embodiment, the condition is selected from condition disclosed herein.

The present invention also provides a method for treating or preventing coronavirus induced respiratory complications, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.

The present disclosure encompasses all subjects having or at risk of coronavirus infection. The subject may be suffering from a symptom or complication of a coronavirus infection, or may be asymptomatic. The subject may have been diagnosed with a coronavirus infection or may be suspected of having a coronavirus infection.

Without wishing to be bound by theory, a subject with a symptom of a coronavirus injection, or a symptom attributable to a coronavirus infection (i.e. the subject may or may not have been tested for a coronavirus infection) can treated by a method of the present invention.

Diagnosis or confirmation of a coronavirus infection (e.g. COVID-19) can be carried out by the skilled clinician. There are at least two methods to test a subject for a coronavirus infection. One test can detect the presence of the virus currently in the subject (e.g. a PCR (polymerase chain reaction) test) and a second test that can detect a previous response to the virus by a subject's immune system (e.g. an antibody test). The PCR test may confirm that the virus is currently in a subject, by detecting the presence of the viral RNA in e.g. a sample from the subject's nose and/or throat. The antibody test can analyse a blood sample from the subject to determine whether a subject's immune system has previously responded to the virus already. The PCR test and/or the antibody test can be used to diagnose a subject with a coronavirus infection. A chest CT or a radiograph scan can also be used to confirm coronavirus infection.

In an embodiment, a subject in need of treatment by the present invention has a confirmed SARS-Cov-2 infection (e.g. confirmed by PCR from a nasopharyngeal or lower respiratory tract sample).

In an embodiment, a subject in need of treatment by the present invention has lung imaging showing pulmonary infiltrates consistent with COVID-19 lung disease (e.g. imaging can be undertaken by a chest X-ray or CT scan). A pulmonary infiltrate can be a substance denser than air, such as pus, blood, or protein, which lingers within the parenchyma of the lungs.

In certain embodiments, the subject has risk factors for aggravated severity of the infection. Risk factors include co-morbidities such as obesity, hypertension, or diabetes (e.g. type 2 diabetes). Subjects at greater risk include those over 65 years of age, and those in black, Asian and minority ethnic groups. In an embodiment, the subject has one more risk factors selected from being over 65, being in a black, Asian and/or a minority ethnic group, having obesity, hypertension, and/or diabetes (such as type 2 diabetes). In an embodiment, the subject is in a black, Asian and/or a minority ethnic group.

There are reports of coronavirus causing severe complications in paediatric subjects. In an embodiment, the subject is a paediatric subject. In an embodiment, the subject is less than 18 years of age.

In particular, a complication in the paediatric population may be an inflammatory disease, disorder or syndrome. The inflammatory disease, disorder or syndrome may be a complication from a coronavirus infection. Without wishing to be bound by theory, a coronavirus infection may cause an inflammatory disease, disorder or syndrome in the paediatric population a pathway that involves neutrophils and neutrophil extracellular traps (NETs).

The present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome in a paediatric subject. The present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome in a paediatric subject with a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome associated with a coronavirus infection in a paediatric subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof. The present invention provides a method for the treatment or prevention of an inflammatory disease, disorder or syndrome arising as a symptom or complication of a coronavirus infection in a paediatric subject, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.

Kawasaki disease is a syndrome of unknown cause that can result in a fever and mainly affects paediatric subjects. Kawasaki disease may be a form of vasculitis. This is where blood vessels become inflamed throughout the body.

In some embodiments, the inflammatory disease, disorder or syndrome is Kawasaki disease. In some embodiments, the inflammatory disease, disorder or syndrome is similar to Kawasaki disease.

In some embodiments, the inflammatory disease, disorder or syndrome is Paediatric Inflammatory Multisystem Syndrome. In some embodiments, the inflammatory disease, disorder or syndrome is Paediatric Inflammatory Multisystem Syndrome Temporally associated with coronavirus. In some embodiments, the inflammatory disease, disorder or syndrome is Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS).

PIMS-TS signs and/or symptoms can include abdominal pains, diarrhoea and/or fever. Subjects with PIMS-TS show more biomarkers of inflammation and/or cardiac enzymes. This is suggestive that the heart is under strain. In some embodiments, the subject has PIMS-TS and a cardiac disorder.

In an embodiment, the subject requires hospitalisation. Hospitalisation refers to the admission to hospital for treatment. In an embodiment, the subject requires ventilation. In an embodiment, the ventilation is mechanical ventilation. In other embodiments, the subject does not require ventilation.

The WHO 9 point ordinal scale for the clinical improvement of patients diagnosed with SARS-CoV-2 (COVID-19) is:

-   -   0. Uninfected, no clinical or virological evidence of infection     -   1. Ambulatory, no limitation of activities     -   2. Ambulatory, limitation of activities     -   3. Hospitalized—mild disease, no oxygen therapy     -   4. Hospitalized—mild disease, oxygen by mask or nasal prongs     -   5. Hospitalized—severe disease, noninvasive ventilation or high         flow oxygen     -   6. Hospitalized—severe disease, intubation and mechanical         ventilation     -   7. Hospitalized—severe disease, ventilation and additional organ         support—vasopressors, renal replacement therapy, extracorporeal         membrane oxygenation     -   8. Death.

Noninvasive ventilation can refer to the administration of ventilatory support without using an invasive artificial airway (endotracheal tube or tracheostomy tube). For example, non-invasive ventilation can involve the use of breathing support administered through a face mask, nasal mask, or a helmet. Air, optionally with added oxygen, can be given through the mask device, optimally under positive pressure. Intubation can be the process of inserting a tube, called an endotracheal tube, through the mouth and then into the airway. Intubation may be done so that a subject can be placed on a ventilator to assist with breathing.

In an embodiment, a subject in need of treatment by the method of present invention has a score of Grade 3 to 5 on the WHO 9-point Ordinal Scale.

Methods according to the invention also comprise improving or preventing worsening of the condition of the subject on the WHO 9-Point Ordinal Scale.

In an embodiment, the method for treatment of a coronavirus infection comprises improving or preventing worsening of the condition of the subject according to the WHO 9-point ordinal scale. In an embodiment, the method comprises improving the condition of the subject by at least 1 point according to the WHO 9-point ordinal scale. In an embodiment, the method comprising improving the condition of the subject by at least 2 points according to the WHO 9-point ordinal scale. In an embodiment, the subject has a score of Grade 3 on the WHO 9-point Ordinal Scale prior to starting treatment. In an embodiment, the subject has a score of Grade 4 on the WHO 9-point Ordinal Scale prior to starting treatment. In an embodiment, the subject has a score of Grade 5 on the WHO 9-point Ordinal Scale prior to starting treatment. In an embodiment, the subject has a score of Grade 3 to 5 on the WHO 9-point Ordinal Scale prior to starting treatment. In an embodiment, the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 29 days of treatment. In an embodiment, the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 20 days of treatment. In an embodiment, the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 10 days of treatment. In an embodiment, the improvement or prevention of worsening according to the WHO 9-point ordinal scale occurs in less than or equal to 5 days of treatment.

Thus in embodiments relating to treatment of a coronavirus infection, treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof improves the grading by at least 1 grade according to the WHO 9-point ordinal scale. In further embodiments, treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof prevents the grading from worsening.

A biomarker can be a measurable indicator of the severity or presence of a disease state. Relevant blood biomarkers can be used to detect signals of effect. Term “biomarker” may be used interchangeably with “blood biomarker” in the present disclosure.

In an embodiment, one or more blood biomarkers can be used to characterize the effect of alvelestat on blood pharmacodynamic markers of Neutrophil Extracellular Trap (NET) activation, elastase, inflammatory and/or coagulopathy activity. In an embodiment, the effect is characterized relative to the baseline level of the biomarker in a blood sample from a subject prior to treatment according to the present invention. In an embodiment, the change from baseline level of the biomarker is determined over a relevant treatment period, for example 10 days of treatment.

Acute-phase proteins (APPs) can be a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response can be called the acute-phase response. The acute-phase reaction can involves fever, acceleration of peripheral leukocytes, circulating neutrophils and their precursors. A coronavirus infection (e.g. COVID-19) can cause an acute phase response in a subject. In an embodiment, the subject in need of treatment has an acute phase response. In an embodiment, the subject in need of treatment may have an acute phase response. In an embodiment, the subject in need of treatment may exhibit neutrophil activation (e.g. increased C-reactive protein and/or absolute neutrophilia). In an embodiment, the subject in need of treatment may have an activated NETosis pathway.

In an embodiment, the subject may have an acute innate inflammatory response, optionally in response to a coronavirus (e.g. COVID-19) infection. In an embodiment, the acute innate inflammatory response comprises one or more of elevated pro-inflammatory cytokines, elevation of acute phase reactants and/or cytokine storm.

Without wishing to be bound by theory, a subject with a coronavirus infection may display one or more of increased levels of inflammation, increased levels of coagulation activation products, increased levels neutrophils, increased levels of neutrophil elastase activity, increased levels of NETs, and increased levels of NETosis. At least an increased level of NETs (and by analogy neutrophils, NETosis, neutrophil elastase activity, and inflammation) may cause increased levels of cytokines, and optionally a cytokine storm, by various pathways. All the neutrophil, neutrophil elastase and NET related pathways may manifest in or contribute to diseases or conditions, such as ARDS. Therefore, a subject displaying increased levels of inflammation, increased levels of neutrophils, increased levels of neutrophil elastase activity, increased levels of NETs, and/or increased levels of NETosis, may be in need of the methods of treatment of the present invention. Levels/activities can be determined by analyzing one or more blood biomarkers in the subject.

In an embodiment, the subject may have increased neutrophil elastase activity. In an embodiment, the subject may have increased levels of NETosis. In an embodiment, the subject may have increased levels of NETs. In an embodiment, the subject may have inflammation, optionally lung inflammation. In an embodiment, the increased levels, activity and/or inflammation may be present in the subject prior to treatment by the method for treatment of the present invention. In an embodiment, the increased levels, activity and/or inflammation may be determined prior to treatment.

In an embodiment, the increased levels, activity and/or inflammation may be determined by one or more blood biomarkers. In an embodiment, the neutrophil elastase inhibition or change in activity may be determined by one or more blood biomarkers. In an embodiment, the one or more blood biomarker are plasma desmosine isodesmosine, and/or A-alpha-Val (A-alpha-Val360). In an embodiment, the one or more blood biomarkers are selected from the group consisting of cell-free DNA, citrullinated histone H3, Myeloperoxidase (MPO), Myeloperoxidase (MPO)-DNA complexes, and Proteinase-3. In an embodiment, the one or more blood biomarkers are selected from the group consisting of absolute and/or percentage neutrophil count, absolute and/or percentage lymphocyte count, neutrophil-lymphocyte ratio [NLR], Erythrocyte Sedimentation Rate (ESR), C-Reactive protein, fibrinogen, complement components (e.g. C2, C4, C3, C5), Total Hemolytic complement, complement breakdown products (e.g. C3a, C3b, C4a, C4b), procalcitonin, pro-inflammatory cytokines (e.g. selected from IL-1beta, IL-6, IL-8, and TNF-alpha), and D-Dimer. In an embodiment, the one or more blood biomarkers are measured by markers of inflammation. In an embodiment, the markers of inflammation are selected from proinflammatory cytokines (e.g. selected from IL-1beta, IL-6, IL-8 and TNF-alpha) and coagulopathy (d-dimer, prothrombin, thrombin, plasmin, P-selectin, clotting and bleeding times, von Willebrand Factor, and platelet count).

In an embodiment, one or more blood biomarkers can be used to characterize the inhibition and/or reduction of the formation of NETs or NET activation.

In an embodiment, one or more blood biomarkers can be used to characterize the inhibition and/or reduction of NETosis (e.g. at least one of cell-free DNA; citrullinated histone H3; Myeloperoxidase (MPO); Myeloperoxidase (MPO)-DNA complexes; and Proteinase-3).

In an embodiment, one or more blood biomarkers can be used to characterize the inhibition and/or reduction of neutrophils or neutrophil elastase activity. In an embodiment, one or more blood biomarkers can be used to characterize the inhibition and/or reduction of inflammation (e.g. at least one of absolute neutrophil count; absolute lymphocyte count; neutrophil-lymphocyte ratio [NLR]; Erythrocyte Sedimentation Rate (ESR); C-Reactive protein; fibrinogen, complement components (e.g. C2, C4, C3, C5), Total Hemolytic complement, complement breakdown products (e.g. C3a, C3b, C4a, C4b); and/or procalcitonin).

In an embodiment, one or more blood biomarkers can be used to characterize the inhibition and/or reduction of pro-inflammatory cytokines (e.g. at least one of IL-1beta, IL-6, IL-8, and/or TNF-alpha).

In an embodiment, one or more blood biomarkers can be used to characterize the inhibition and/or reduction of coagulopathy (e.g. as measured by one or more of D-Dimer, prothrombin, thrombin, plasmin, P-selectin, clotting and bleeding times, von Willebrand Factor, and/or platelet count).

In an embodiment, blood biomarkers can be used to characterize the inhibition and/or reduction of plasma desmosine, isodesmosine, and/or A-alpha-Val.

As mentioned above, some diseases or conditions, e.g. ARDS, can be diagnosed by PaO₂/FiO₂, SaO₂/FiO₂ and/or SpO₂. PaO₂/FiO₂, SaO₂/FiO₂ and/or SpO₂ may also be general indicators of respiratory issues when the subject has a coronavirus infection. PaO₂/FiO₂ is the ratio of partial pressure arterial oxygen (PaO₂) and fraction of inspired oxygen (FiO₂). PaO₂/FiO₂ is a comparison between the oxygen level in the blood and the oxygen concentration that is breathed. This may help determine the degree of any problems with how the lungs transfer oxygen to the blood. The PaO₂/FiO₂ (and the SaO₂/FiO₂) ratio is a parameter to assess respiratory dysfunction.

A PaO₂/FiO₂ ratio less than about 300 can be used to confirm a diagnosis of a disease or condition, e.g. ARDS. A PaO₂/FiO₂ ratio of about 200-about 300 may confirm a diagnosis of disease or condition, e.g. ARDS. A subject requiring treatment according to the present invention may have a PaO₂/FiO₂ ratio less than about 300.

SaO₂ refers to arterial oxygen saturation, and can be determined by an arterial blood gas test. Pulse oximetry can be used to estimate the percentage of oxygen bound to hemoglobin in the blood, e.g. arterial oxygen saturation. The ratio of O₂ saturation to fraction inspired O₂ (SaO₂/FiO₂) is a reliable, non-invasive surrogate for PaO₂/FiO₂. SaO₂/FiO₂ can be predictive for 3-day worsening in patients with coronavirus infection (e.g. a COVID-19 infection). A SaO₂/FiO₂ ratio of about 200-about 300 may confirm a diagnosis of a disease or condition, e.g. ARDS.

A subject requiring treatment according to the present invention may have a SaO₂/FiO₂ ratio less than about 300. In some embodiments, the methods of the invention lead to an improvement or the prevention of worsening in SaO₂/FiO₂ (or PaO₂/FiO₂), e.g. an increase in the SaO₂/FiO₂ (or PaO₂/FiO₂). In an embodiment, SaO₂/FiO₂ (or PaO₂/FiO₂) is less than about 300. In an embodiment, SaO₂/FiO₂ (or PaO₂/FiO₂) is about 300 to about 200. In an embodiment, SaO₂/FiO₂ (or PaO₂/FiO₂) is about 200 to about 100. In an embodiment, SaO₂/FiO₂ (or PaO₂/FiO₂) is about 100 to about 200.

Pulse oximetry can be used to approximate SaO₂. Pulse oximetry be can be used to determine SpO₂ (peripheral oxygen saturation). Therefore, a pulse oximeter can be also used to approximate SaO₂. An SaO₂ or SpO₂ of about 95-100% is a normal arterial blood oxygen saturation level in a subject. An SaO₂ or SpO₂ of less than or equal to about 95% may indicate that a subject is in need of a method of treatment provided by the present invention.

Methods according to the invention, may also comprise improving one or more pulmonary function parameters in a subject.

In particular, methods according to the invention may improve or prevent worsening of SaO₂/FiO₂ of a subject.

Accordingly, also provided is a method for increasing SaO₂/FiO₂ in a subject with a coronavirus infection, by administering an effective amount of a NE inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the coronavirus is SARS-COV, e.g. COVID-19.

In particular embodiments, treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof increases SaO₂/FiO₂ by at least about 1%, 1.5%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 15%, 20%, 30%, 40% or 50% compared to a baseline SaO₂/FiO₂ measurement. In an embodiment, the baseline measurement may be measured on day 1 of the treatment. In an embodiment, the change in SaO₂/FiO₂ measurement is the change in the baseline measurement over a relevant treatment period, e.g. over 10 days of treatment.

In further embodiments, treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof prevents SaO₂/FiO₂ from worsening.

Other parameters can be used to determine lung function, improvements in lung function, or the worsening of lung function. For example, one parameter is the forced expiratory volume in 1 second (FEV1), which is the volume of air (in liters) exhaled in the first second during forced exhalation after maximal inspiration.

In an embodiment, the method for treatment comprises improving or preventing worsening of forced expiratory volume in 1 second (FEV1) in the subject. In an embodiment, an improvement is where the volume increases relative to baseline level in the subject measured prior to treatment. As set out above, and without wishing to be bound by theory, alvelestat is beneficial in the methods of the invention due to its ability to inhibit neutrophil elastase, NETs and/or NETosis.

Accordingly, the invention also provides methods of inhibiting neutrophil elastase, NETs and/or NETosis in a subject suffering from, or at risk of, any of the conditions described herein, including a coronavirus infection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.

The present invention also provides alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for use in a method of treating a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19. Any embodiment of the present invention which relates to a method of treatment. For each and every method in this disclosure, the invention provides a further embodiment relating to alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for use in that method.

Also provided is the use of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for manufacture of a medicament for treating a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19. For each and every method in this disclosure, the invention provides a further embodiment relating to the use of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for that method.

Dosing

For the above mentioned therapeutic indications, the dose of the neutrophil inhibitor to be administered, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, will depend on the disease being treated, the severity of the disease, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient).

Suitably the daily dose is from 0.5 to 1000 mg per day, for example from 50 to 800 mg per day, in particular 50 to 600 mg per day, more particularly 120 mg to 550 mg, even more particularly 200 to 500 mg. For example the daily dose is about 240, 270, 300, 330, 360, 390, 420, 450 or 480 mg per day. The dose may be administered as a single dose or as a divided dose, for example wherein the total daily dose is divided in to two or more fractions, administered during the day. A dose may be administered daily, or multiple times a day (for example twice daily), or multiple times a week, or monthly, or multiple times a month.

In a particular embodiment alvelestat or a pharmaceutically acceptable salt and/or solvate thereof is administered twice a day (BID dosing). In a further embodiment alvelestat or a pharmaceutically acceptable salt and/or solvate thereof is administered twice a day, wherein each dose is equivalent to up to 240 mg of alvelestat free base, for example 60 mg twice a day, 90 mg twice a day, 120 mg twice a day, 150 mg twice a day, 180 mg twice a day, 210 mg twice a day, or 240 mg twice a day. In particular, 240 mg is administered twice a day.

Compounds may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration. For example, for between about one day and four weeks, for between about one week and two weeks.

Preferably, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered for about 10 days. For example, for 10 days at a twice daily dose equivalent of up to 240 mg of alvelestat free base.

In preferred embodiments of the invention, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 10 days, wherein each dose on day 1 of treatment is equivalent to 120 mg, wherein each dose on day 2 of treatment is equivalent to 180 mg, and wherein each dose on days 3-10 of treatment is equivalent to 240 mg.

In an embodiment, on day 1 the subject has 120 mg bid (4×30 mg tablets bid). In an embodiment, on day 2 the subject has 180 mg bid (6×30 mg tablets bid). In an embodiment, on days 3-10 the subject has 240 mg bid (8×30 mg tablets bid).

In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for a duration longer than 10 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for a duration longer than 10 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 14 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 30 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 60 days. In an embodiment, alvelestat or a pharmaceutically acceptable salt or solvate thereof is administered twice daily for 1 to 90 days.

Compositions

The neutrophil inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, can be administered to a subject in the form of a pharmaceutical composition.

Accordingly, the invention provides a method of treating or preventing any of the conditions described herein comprising administering a pharmaceutical composition comprising an effective amount of a neutrophil inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable excipients, to a subject in need thereof.

Pharmaceutical compositions may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accord with ordinary practice.

“Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans. All compositions may optionally contain excipients such as those set forth in the Shesky et al, Handbook of Pharmaceutical Excipients, 8^(th) edition, 2017. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.

Pharmaceutical compositions include those suitable for various administration routes, including oral administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 22^(nd) Edition, 2012.

A preferred pharmaceutical composition is a solid dosage form, including a solid oral dosage form, such as a tablet. Tablets may contain excipients including glidants, fillers, binders and the like.

In effecting the methods described herein, the pharmaceutical compositions can be administered in any form and route which makes the compound bioavailable. Thus, the pharmaceutical compositions can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, intraadiposally, intrathecally and via local delivery for example by catheter or stent. Preferably, the pharmaceutical compositions are administered orally.

When used for oral use, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Preferably, the pharmaceutical composition is a tablet.

Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic.

The amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the particular mode of administration.

Combination Therapy

In the present invention, the methods may further include the step of administering to the subject one or more (e.g. 1, 2, 3 or 4) additional therapeutic agents. The administration of the one or more additional therapeutic agents may occur prior to, concurrently with, or after the administration of the neutrophil inhibitor. The neutrophil inhibitor, e.g. alvelestat or a pharmaceutically acceptable salt or solvate thereof, can also be administered in combination with any standard of care appropriate for a coronavirus infection, e.g. COVID-19.

Therapies to assist in the methods according to the present invention (e.g. treat a symptom and/or complication of COVID-19) can be selected from organ support, anti-coagulation treatment (e.g. to reduce risk of venous and arterial thrombosis), treatment of infection, and/or treatment of sepsis. In an embodiment, organ support, anti-coagulation, treatment of infection, and/or sepsis can be combined with the methods for treatment of the present invention.

The one or more additional therapeutic agents may be any therapeutic agent. In particular, the one or more additional therapeutic agent may be selected from the group consisting of an antiviral agent, an anti-TNF agent, an anti-inflammatory agent, an analgesic agent, a steroid, an antibody, an immunosuppressive agent, a vaccine, an antimalarial agent, and an enzymatic agent.

One or more additional therapeutic agents can be selected from those approved in treating a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19. In an embodiment, one or more additional therapeutic agents can be selected from remdesivir, nitric oxide, lopinavir and ritonavir, favipiravir, atlizumab, angiotensin II, interferon (e.g. inhaled interferon) dexamethasone, and hydroxychloroquine. In an embodiment, the one or more additional therapeutic agents is remdesivir or a pharmaceutically acceptable salt thereof. In an embodiment, the one or more additional therapeutic agents is dexamethasone or a pharmaceutically acceptable salt thereof. In an embodiment, the one or more additional therapeutic agents is interferon (e.g. inhaled interferon) or a pharmaceutically acceptable salt thereof. In an embodiment, the one or more additional therapeutic agents is Sivelestat or a pharmaceutically acceptable salt thereof.

One or more additional therapeutic agents can be selected from those undergoing clinical trials for treating of a coronavirus infection and/or preventing progression of a coronavirus disease, e.g. COVID-19. In an embodiment, the one or more additional therapeutic agents can be selected from: immunotherapy with anti-COVID-19 antibodies, BPI-002, Ifenprodil, Brilacidin, Duvelisib, Tramadol, C21, Deferoxamine, Azithromycin, Methylprednisolone, Chlorpromazine, Enoxaparin, DAS181, Isotretinoin, Sirolimus, Lactoferrin, Clopidogrel, Rivaroxaba, Clevudine, MCN (Methylene blue, vitamin C, N-acetyl cysteine), Pegylated interferon lambda, CPI-006, epoprostenol, Recombinant Bacterial ACE2 receptors, Recombinant Human ACE2, heparin, Fondapariniux, Argatroban, TXA127, AG0301-COVID19, Baricitinib, 13 cis retinoic acid, All trans retinoic acid, ABX464, Clazakizumab, IFX-1, camostat mesilate, mavrilimumab, Pamrevlumab, Povidone-iodine, Zanubrutinib, Famotidine, Nitazoxanide and atazanavir/ritonavir, Losartan, Ivermectin, Dapagliflozin, REGN10933+REGN10987, Recombinant human angiotensin-converting enzyme 2 (rhACE2), Bemiparin, Ozanimod, Naproxen, Intravenous Immune Globulin, Plitidepsin, Colchicine, Interferon beta-1b, Clofazimine, Ruxolitinib, NK cells, IL15-NK cells, NKG2D CAR-NK cells, ACE2 CAR-NK cells, NKG2D-ACE2 CAR-NK cells, Acalabrutinib, Sarilumab, BDB-001, Nafamostat, Telmisartan, Thymalfasin, Interferon Beta-1A, Bicalutamide, Ciclesonide, Doxycycline, Anakinra, Estradiol, Prazosin, Pentoxifylline, Rivaroxaban, Umifenovir, MRx-4DP0004, Crizanlizumab, Siltuximab, Tetrandrine, avdoralimab, Olokizumab, lanadelumab, Pacritinib, Montelukast, Sargramostim, Apilimod, Sildenafil, Zilucoplan, OP-101, Gimsilumab, TJM2 (a neutralising antibody), TZLS-501 (a monoclonal antibody), leronlimab, Infliximab, Tocilizumab, chloroquine, hydroxychloroquine, APN01, Dornase alfa, dexamethasone, ibuprofen, paracetamol, aspirin, Bivalirudin, AT-001, Probiorinse, SCB-2019, Amiodarone, Verapamil, Atorvastatin, Angiotensin peptide (1-7) derived plasma, CAP-1002, Etoposide, Tofacitinib, AVM0703, hydrocortisone, Tranexamic acid, Bromhexine, Imatinib, Lenalidomide, N-Acetyl cysteine, Dipyridamole, lactoferrin, Ravulizumab, Atovaquone, Simvastatin, PHR160, Ulinastatin, Melatonin, RhACE2 APN01, XPro1595, AT-527, EDP1815, Ambrisentan, Methotrexate, Degarelix, LY3819253, BAT2020, Quercetin, N-803, STI-1499, RBT-9, Levilimab, Peginterferon Lambda-1a, Levamisole, Formoterol, Budesonide, Abivertinib, AV-COVID-19, PUL-042, Defibrotide, Virazole, RTB101, co-trimoxazole, nangibotide, RESP301, Vazegepant, IC14, Enzalutamide, Bevacizumab, Human immunoglobulin, immunoglobulin, Fluvoxamine, DFV890, MSTT1041A, Sofusbuvir, Camostat, LAU-7b, thalidomide, metenkefalin, tridecactide, MAS825, SAB-185, Nivolumab, Sirukumab, MV130, Indomethacin, Iloprost, Lenzilumab, TD-0903, ATYR1923, Silymarin, Imitrine, Isoprinosine, Eculizumab, TJ003234, Fluoxetine, Octagam, CD24Fc, Garadacimab, Dociparastat, NK-1R antagonist, CK0802, Recombinant human plasma gelsolin (Rhu-pGSN), Diphenhydramine, Oxytocin, ANG-3777, AMY-101, ACE inhibitors (ACEls), angiotensin receptor blockers, LEAF-4L6715, LEAF-4L7520, Lucinactant, Opaganib, poractant alfa, Ethyl eicosapentaenoic acid, Interleukin-7, SBI-101, Pyridostigmine Bromide, Artemisinin, Artesunate, CYT107, BLD-2660, Sevoflurane, IMM-101, GLS-1200, Prasugrel, HB-adMSCs, P2Et (Caesalpinia spinosa extract), LB1148, Dexmedetomidine, TY027, BMS-986253, PTC299, Hidroxicloroquina, CERC-002, captopril, DUR-928, DeltaRex-G, Valsartan, ArtemiC, aviptadil, MK-5475, ASC09F, Thiazidem, NA-831, Naltrexone, Ketamine, Nintedanib, Calcifediol, Secukinumab, PB1046, T89, MenACWY, Leronlimab, azoximer bromide, SNDX-6352, TL-895, Linagliptin, Alteplase, Ibudilast, Ibrutinib, XAV-19, BNT162a1, BNT162b1, BNT162b2, BNT162c2, CM4620, CSTC-Exo, Spironolactone, Conestat alfa, Tirofiban, Acetylsalicylic acid, cholecalciferol, Plaquenil, SAR443122, Pertuzumab, Trastuzumab, Tradipitant, and TAK-981.

The one or more additional therapeutic agents can include immunosuppressive agents, anti-infective agents, anti-inflammatory agents, pain relievers, antiviral agents, steroids, antibodies, vaccines, and enzymatic agents.

In an embodiment, the one or more additional therapeutic agents are immunosuppressive agents. For example, one, two, or preferably three immunosuppressive agents may be administered.

The immunosuppressive agents may, for example, be selected from the group consisting of corticosteroids (e.g. methylprednisolone, prednisone, prednisolone, budesonide, and/or dexamethasone), janus kinase inhibitors (e.g. tofacitinib), calcineurin inhibitors (e.g. cyclosporine, and/or tacrolimus), mTOR inhibitors (e.g. sirolimus, everolimus, and/or temsirolimus), biologics (e.g. abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, and/or vedolizumab), monoclonal antibodies (e.g. basiliximab, and/or daclizumab), tyrosine kinase inhibitors (e.g. imatinib, thalidomide, pentostatin, azathioprine, mycophenolate, and/or methotrexate).

In particular, the neutrophil elastase inhibitor of the invention may be administered with a corticosteroid. In an embodiment, the immunosuppressive agent is a corticosteroid, for example selected from the following types: Hydrocortisone, Acetonides (and related substances), Betamethasone, Halogenated, and/or Prodrug esters. The Hydrocortisone type includes Hydrocortisone, Hydrocortisone acetate, Cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone. The Acetonides (and related substances) include Amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide. The Betamethasone type includes Beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone. The Halogenated type includes Alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate. The Prodrug ester type includes Ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate.

In an embodiment, the one of more therapeutic agents is an anti-TNF agent. In an embodiment, the anti-TNF agent is selected from: infliximab, etanercept, certolizumab, golimumab, adalimumab, adalimumab, Thalidomide, lenalidomide, pomalidomide, pentoxifylline, and/or bupropion.

In certain embodiments, the methods further include the step of administering to the subject a triple combination of immunosuppressive agents, for example tacrolimus, mycophenolate and a corticosteroid.

The one or more additional therapeutic agents may be anti-infective agents. Anti-infective agents include antibiotics, antifungals, anthelmintics, antimalarials, antiprotozoals, antituberculosis agents, and antivirals.

In an embodiment, the one or more additional therapeutic agents are antiviral agents. For example, one, two, or preferably three antivirals agent may be administered.

The antiviral agents may, for example, be selected from the group consisting of Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Arbidol Umifenovir, Atazanavir, Atripla, Baloxavir marboxil (Xofluza), Biktarvy, Boceprevir, Cidofovir, Cobicistat (Tybost), Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Entecavir, Etravirine (Intelence), Famciclovir, Favilavir, Fomivirsen, Fosamprenavir, Foscarnet, Ganciclovir (Cytovene), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Imunovir, Indinavir, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir, Nevirapine, Nexavir formerly (Kutapressin), Nitazoxanide, Norvir, Oseltamivir, OYA1, Penciclovir, Peramivir, Penciclovir, Peramivir (Rapivab), Pleconaril, Podophyllotoxin, Raltegravir, Remdesivir, Ribavirin, Rilpivirine (Edurant), Rilpivirine, Rimantadine, Ritonavir, Saquinavir, Simeprevir (Olysio), Sofosbuvir, Stavudine, Taribavirin (Viramidine), Telaprevir, Telbivudine (Tyzeka), Tenofovir alafenamide, Tenofovir disoproxil, Tenofovir, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Umifenovir, Valaciclovir, Valganciclovir (Valtrex), Vicriviroc, Vidarabine, Zalcitabine, Zanamivir (Relenza), Zidovudine, umifenovir, danoprevir and ritonavir, carrimycin, camostat, baloxavir marboxil, azithromycin, triazayirin, oseltamivir, nitazoxanide, famotidine, emtricitabine and tenofovir disoproxil fumarate, Convalescent Plasma, ASC09 and ritonavir, VERU-111, selinexor, PP-001, piclidenoson, merimepodib, ionafarnib, IMU-838, hyperimmune plasma, galidesivir, FW-1022, Niclosamide, FP-025, fluidase, elsulfavirine, EIDD-2801, clevudine, bemcentinib, azvudine, ATR-002, AQCH, aplidin, LY-CoV555, NKG2D-ACE2 CAR-NK Cells, meplazumab, CYNK-001, brequinar, TY027, NK cells, mefuparib, leflunomide, JS016, FT516, COVID-HIG, and BC007.

In an embodiment, the one or more additional therapeutic agents is a vaccine.

The vaccine may, for example, be selected from the group consisting of VPM1002, MMR vaccine. ChAdOx1 nCoV-19, BCG vaccine, PrEP-001, mRNA-1273, CoronaVac, Ad5-nCoV, a coronavirus-based vaccine, V-SARS, NVX-CoV2372, Inactivated SARS-CoV-2 Vaccine, GX-19, BNT162 mRNA vaccine, AV-COVID-19, ZyCoVD, S-protein vaccine, RUTI vaccine, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA vaccine, CVnCoV vaccine, bacTRL-Spike, TNX-1800, and anti-SARS-CoV-2 convalescent plasma.

Furthermore, the one or more additional therapeutic agents may be selected from the group of prednisone, methylprednisone, budesonide, beclomethasone dipropionate, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, tilomisole, imuthiol, antithymocyte globulin, azathioprine, azodiacarbonide, bisindolyl maleimide VIII, brequinar, chlorambucil, CTLA4-Ig, cyclophosphamide, deoxyspergualin, dexamethasone, leflunomide, mercaptopurine, 6-mercaptopurine, methotrexate, methylprednisolone, mizoribine, mizoribine monophosphate, muromonab CD3, mycophenolate mofetil, OKT3, rho (D) immune globin, vitamin D analogs, MC1288), daclizumab, infliximab, rituximab, tocilizumab alemtuzumab, methotrexate, antithymocyte globulin, denileukin diftitox, Campath-1H, keratinocyte growth factor, abatacept, remestemcel-L suberoylanilide hydroxamic acid, pentostatin, thalidomide, imatinib mesylate, cyclophosphamide, fludarabine, OKT3, melphalan, thiopeta, and lymphocyte immune globulin, anti-thymocyte, and globulin.

In an embodiment, the one or more additional therapeutic agents is an analgesic agent. The analgesic agent may, for example, be selected from the group consisting of acetaminophen, a Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. one or more of ibuprofen, naproxen, and/or celecoxib), paracetamol, acetylsalicylic acid, and/or codeine.

In the present invention, the methods may further include the step of administering to the subject one or more (e.g. 1, 2, 3 or 4) additional therapeutic agents when the subject requires ventilation. In some embodiments, one or more (e.g. 1, 2, 3 or 4) additional therapeutic agents includes a corticosteroid when the subject requires ventilation. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the ventilation is mechanical ventilation.

It is also understood that each of the agents administered individually or combined in a combination therapy or regimen may be administered at an initial dose that may then over time be reduced by a medical professional to reach a lower effective dose.

EXAMPLES

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of methods provided herein, but are not in any way limiting. It will be apparent to those skilled in the art that various changes and modifications may be made. Such modifications are also intended to fall within the scope of the appended claims.

Alvelestat used in the following examples may be synthesised according to WO 2005/026123 A1 (Example 94, page 85).

Example 1—Alvelestat is a Potent and Specific Inhibitor of Neutrophil Elastase (NE)

The following results were obtained as discussed further in [11].

Alvelestat has a high binding affinity for human NE (K_(D)=9.5 nM) and potently inhibits NE activity. The calculated _(p)IC₅₀ (IC₅₀) and K values for alvelestat for human NE are 7.9 (12 nM) and 9.4 nM, respectively.

Alvelestat is at least 600-fold more selective for human NE compared with another serine protease cathepsin G, and at least 1900-fold more selective for human NE comprised with other serine proteases (proteinase-3, chymotrypsin, pancreatic elastase and trypsin).

Alvelestat shows good crossover potency for NE from other species, including mice.

The _(p)IC₅₀ (IC₅₀) values in whole-blood, cell-associated, and explosive-release assays were 7.36 (44 nM), 7.32 (48 nM), and 7.30 (50 nM), respectively.

The results of the studies presented show that alvelestat is a specific, potent, and rapidly reversible inhibitor of human NE. The potent inhibitory activity of alvelestat on NE in biochemical assays was confirmed in whole-blood and cell-based systems.

Example 2—Scientific Rationale

The inventors rationalise that treatment with alvelestat has the potential to be useful in patients with coronavirus infection, in particular SARS-COV such as COVID-19, by impacting progression to ARDS through disruption of NETosis.

Neutrophils and neutrophil extracellular traps (NETs) have recently been established as a central feature of SARS-CoV-2 pathogenesis, and NETosis is associated with poor outcomes in patients hospitalized with COVID-19 ([12], [13], [14]). Levels of NETs correlate with disease severity in ALI/ARDS outside of COVID-19.

NETs are networks of extracellular DNA fibers, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), released from neutrophils and involved physiologically in capturing bacteria. However, if uncontrolled, NETs are cytotoxic to endothelial and epithelial cells; acting as Damage Associated Molecular Pattern Molecules (DAMPs), promoting cytokine release and thromboses ([7]). Neutrophil elastase is essential to NET formation ([6]) and remains active when decorating the NET fibers. The physiological inhibitor of NE is Alpha-1 antitrypsin (AAT), but studies in COVID-19 have shown this to be overwhelmed ([8]).

Alvelestat is an oral, specific, NE inhibitor, with experience in over 1000 healthy volunteers and patients with lung disease. Its safety profile is now well-established. Furthermore, there has been evidence of mechanistic effect of alvelestat in 4-week duration clinical studies of neutrophil-driven diseases (significant decrease in biomarkers of elastase activity and inflammation in cystic fibrosis ([16]), and clinically significant improvement in lung function and inflammation in bronchiectasis ([17]). In experimental models of ARDS, alvelestat protected the lung from inflammation and injury through NET inhibition ([18]). The use of alvelestat is therefore expected to ameliorate and/or prevent lung damage in patients with coronavirus infection, in particular SARS-COV, such as COVID-19.

The scientific rationale for NE inhibition in SARS-CoV-2 infection, plus the safety profile for alvelestat, supports investigating alvelestat in a Phase Ib/II trial in subjects with COVID-19.

Example 3—Safety, Tolerability and Effect of Alvelestat in COVID-19

Alvelestat is administered as part of a Phase Ib/II single-center, 2:1 randomized, blinded, placebo-controlled, parallel group, first in disease study to evaluate the safety, tolerability, PK and explore mechanism of action and clinical effect of alvelestat in patients hospitalized with proven COVID-19 lung disease. Alvelestat, dosed at 240 mg orally twice per day for 10 days added to standard of care (SoC) is assessed versus placebo added to SoC, in adult patients (≥18 years) with COVID-19 respiratory disease.

As the first study of alvelestat in the COVID-19 patient population, investigation of safety and tolerability are the primary objectives, and are appropriately investigated in a small 15 subject study. Given the severe nature of COVID-19, alvelestat or identical placebo will be dosed on top of full standard of care. A blinded, placebo-controlled design will support interpretation of safety, tolerability and efficacy biomarkers, Historic comparators were not considered as the evolution of the pandemic and changing management of COVID-19 means that a placebo arm recruited in parallel is a more robust approach.

Neutrophils and NETosis play a critical role in the acute inflammatory response and the most appropriate time to intervene is early in its initiation, to reduce the risks of further progression. Therefore, the target population is those with proven SARS-CoV-2, requiring hospitalization, with evidence of pulmonary disease on chest radiograph or Computerised Tomography (CT) or other relevant imaging, but not progressed to severe disease (i.e. not requiring mechanical ventilation or with multi-organ failure) at the point of recruitment. This population is known to have an acute phase response and evidence for neutrophil activation (raised CRP and absolute neutrophilia, with activation of the NETosis pathway ([12]), therefore giving potential to detect a mechanistic signal in the study. At this stage neutrophil elastase may be a key pathogenic driver and its inhibition stand the greatest chance of success.

The duration of dosing will be for 10 days. Deterioration in COVID-lung disease in hospitalized patients to intubation is rapid and bimodal with modes as 3-4 days and 9 days from the date first symptoms recorded ([19]) and even shorter period from date of hospital admission with the most patients worsening within the first 3 days ([20]). Therefore, 10 days treatment will provide NE inhibition to cover the critical risk period.

A within-patient dose-escalation approach commencing at 120 mg bid Day 1, increasing to 180 mg bid Day 2 and 240 mg bid Days 3 to 10, will be used to address tolerability (headache) issues that have been identified for alvelestat. In association with the short-term dosing, it is anticipated that this approach will be successful in supporting patients to complete the course. Dose de-escalation, including to 120 mg bid, will be allowed if required for toleration as 120 mg bid is still predicted to provide adequate NE inhibition. Dose de-escalation below 120 mg bid will not be permitted.

Objectives and Endpoints

Objective Endpoint Primary To evaluate the safety and tolerability of By treatment group (alvelestat/placebo): alvelestat administered twice daily (bid) for Numbers and % of subjects who experience 10 days at least 1 treatment-emergent adverse event to Day 10 (acute treatment period) or End of Treatment (EoT) Adverse events of special interest (liver function abnormalities, corrected QT interval, infections, and neutropenia) and clinically significant safety monitoring labs tests to Day 10 (acute treatment period) or EoT Numbers and % of subjects who experience at least 1 treatment-emergent adverse event from EoT to Day 29 (Final Outcome Assessment) Numbers and % of subjects that discontinue alvelestat to Day 10 Secondary To evaluate the effect of alvelestat on blood By treatment group (alvelestat/placebo), change pharmacodynamic markers of Neutrophil from baseline to Day 10 in: Extracellular Trap (NET) activation, elastase, Blood biomarkers of NETosis (cell-free DNA; inflammatory and coagulopathy activity citrullinated histone H3; Myeloperoxidase (MPO)-DNA complexes) Blood biomarkers of inflammation (absolute neutrophil count; absolute lymphocyte count; neutrophil-lymphocyte ratio [NLR], C- Reactive protein, fibrinogen, procalcitonin Pro-inflammatory cytokines IL-1beta, IL-6, IL-8, TNF-alpha) Coagulopathy as measured by D-Dimer Plasma desmosine/isodesmosine To explore the effect of alvelestat on By treatment group (alvelestat/placebo): pulmonary function Change from baseline to Day 10 in SaO₂/FiO₂ The effect of alvelestat on clinical outcomes By treatment group (alvelestat/placebo): Percentage of patients deteriorating (>1 and >2 increase in WHO 9-point ordinal scale*) at Day 10/EoT and Day 29 (Final Outcome Assessment) Percentage of patients improving (>1 and >2 decrease in WHO 9-point ordinal scale) at Day 10/EoT and Day 29 (Final Outcome Assessment) To explore Pharmacokinetics (PK) in patients Plasma PK (sparse sampling taken pre and 1-2 with COVID-19 hours post study drug dosing) in participants randomized to alvelestat.

Alvelestat will show effectiveness in one or more of the above endpoints.

Study Design

The study is divided into 3 periods: a screening period, treatment period, and follow up period:

A screening period from Day −2 to randomization. Eligibility assessments and written informed consent will occur prior to randomization and treatment arm allocation. Serious Adverse Events will be collected during screening.

A treatment period consisting of within-subject dose-escalation of alvelestat/matched placebo 120 mg bid Day 1, 180 mg/matched placebo bid Day 2 and 240 mg/matched placebo bid Days 3 to 10 given on top of standard of care (SoC—per local clinical guidelines). Safety assessments including vital signs, liver and renal function, EKG, and hematology, will be assessed at baseline, then as per the Schedule of Assessments (SoA) for the remainder of the 10-day treatment period. Adverse events and concomitant medications will be collected daily. Blood will be collected at baseline during study drug treatment for exploratory efficacy biomarkers and oxygen deficit assessments (SaO2/FiO2). PK sampling will be collected on 4 occasions, at initiation of dosing, at the 2 dose escalation steps and at end of treatment (EoT) for steady state analysis. The clinical outcome (WHO ordinal scale) will be completed during the treatment period at Baseline (Day 1), and EoT (Day 10). Those subjects who are unable to complete the treatment period for any reason, including those discharged from hospital prior to completion of Day 10, will discontinue study drug and undergo an EoT assessment.

A follow-up period from Day 10/EoT to Day 29. This is for safety testing to end of systemic drug exposure (Day 14, or 4 days after EoT) and for the Final Outcome Assessment (FOA) (Day 29) collection of the clinical outcomes endpoint (WHO ordinal scale) which may be by telehealth visit.

Study Population

Approximately 20 subjects will be screened in order to recruit 15 (10 randomized to alvelestat+SoC; 5 randomized to SoC). Subjects who complete <3 days of study drug treatment may be replaced.

Inclusion Criteria

Participants are eligible to be included in the study only if ALL of the following criteria apply:

Type of Participant and Disease Characteristics

-   -   Male or Female     -   Age ≥18 years     -   Proven SARS-Cov-2 infection (confirmed by PCR from a         nasopharyngeal or lower respiratory tract sample)     -   Lung imaging showing pulmonary infiltrates consistent with         COVID-19 lung disease (e.g. chest X-ray or CT scan) prior to         randomization     -   A score of Grade 3 to 5 on the WHO 9-point Ordinal Scale     -   Male participants must agree to use a highly effective         contraception during the treatment period and for at least 4         days after the last dose of study treatment and refrain from         donating sperm during this period     -   Female participants are eligible to participate if not pregnant;         not breastfeeding; and at least one of the following conditions         is met:         -   Not a woman of childbearing potential             -   OR         -   A woman of childbearing potential who agrees to follow             contraceptive guidance. During the treatment phase and for             at least 4 days after the last dose of study medication     -   Capable of giving signed informed consent.

Exclusion Criteria

Participants are excluded from the study if ANY of the following criteria apply:

-   1. Patients who have previously had a score of 6 or 7 on the WHO     9-point Ordinal Scale -   2. Patients who require support with invasive mechanical ventilation     at the time of inclusion, or expected to be required within 24 hours     of randomization -   3. Alanine aminotransferase (ALT) OR aspartate aminotransferase     (AST) >3×the upper limit of normal (ULN) OR Total Bilirubin >2×ULN     (unless Gilbert's Syndrome) -   4. Diagnosis of liver cirrhosis, esophageal varices, ascites or     hepatic encephalopathy -   5. Chronic liver diseases such as autoimmune hepatitis, primary     biliary cholangitis, primary sclerosing cholangitis, Wilson's     disease, haemochromatosis -   6. Significant renal disease or infection (as determined by the     Investigator) including stage 4 chronic kidney disease or estimated     glomerular filtration rate <45 mL/min -   7. Absolute neutrophil count ≤1000/μL at screening -   8. Myocardial infarction, transient ischemic attack or stroke within     3 months prior to the first dose -   9. Current unstable angina or congestive heart failure (New York     Heart Association III/IV) -   10. Screening 12-lead EKG with a measurable QTc interval according     to Fridericia correction (QTcF) >450 ms -   11. Anticipated transfer to another hospital that is not the study     center within 24 hours -   12. Allergy to study medication or excipients -   13. Inability to swallow tablets -   14. Other documented comorbidities or laboratory abnormalities that     in the opinion of the Investigator could affect the outcome of the     study assessments, participant safety, or ability of the participant     to comply with the requirements of the protocol -   15. Any patient whose interests are not best served by study     participation, as determined by the Investigator

Excluded Prior/Concomitant Therapy

-   16. Requirement for medications mainly metabolized by CYP2C9 and     with narrow therapeutic index (eg, warfarin, phenytoin) is     prohibited unless therapeutic monitoring available for duration of     alvelestat dosing -   17. Requirement for medications substantially reliant on OATP1B1 for     metabolism where discontinuation during study drug administration is     not possible or where fluctuations in levels are considered     clinically important (as per investigator judgement) and cannot be     clinically monitored (e.g., statins, valsartan, olmesartan,     enalapril, repaglinide)

Excluded Prior/Concurrent Clinical Study Experience

-   18. Participation in any clinical investigation using     investigational treatments within 4 weeks or 5 half-lives of the     drug (whichever is longer) prior to the initial dosing (or longer if     required by local regulations) is prohibited. Use of remdesivir     (Veklury) under the conditions of the authorization for emergency     use in the US, and per manufacturers instructions, is permitted.

Lifestyle Restrictions

-   19. There are no specific restrictions in respect of mealtimes and     administration of study treatment. -   20. Participants should avoid alcohol during the 10 days of study     drug dosing. -   21. Subjects should not participate in unaccustomed or more vigorous     exercise than usual routine in the 48 hours before each blood sample     for laboratory safety tests.

Treatments

All participants will be randomized via a random allocation to alvelestat or placebo arms to meet enrolment needs of the study.

Participants in the alvelestat and placebo arms are administered treatments according to the following table:

Study Treatment Name: 30 mg alvelestat tablets Placebo Dosage Formulation: Tablet Tablet (identical in appearance to active) Unit Dose Day 1: 120 mg bid (4 × Day 1: 4 × 30 mg tablets bid Strength(s)/Dosage 30 mg tablets bid) Day 2: 6 × 30 mg tablets bid Level(s): Day 2: 180 mg bid (6 × Days 3-10: 8 × 30 mg tablets bid 30 mg tablets bid) Days 3-10: 240 mg bid (8 × 30 mg tablets bid) Route of Administration Oral Oral Dosing Instructions: To be taken bid, 12 hours apart

The placebo and alvelestat tablets are indistinguishable. Investigator, site study team, and participants will remain blinded to the study treatment allocation until the end of the study.

Treatment required for medical management of COVID-19 and co-morbidities is allowed throughout the study, apart from protocol defined prohibited medications. Other investigational treatments may be started after systemic clearance of alvelestat i.e. 4 days from last dose in discussion with the PI.

Key Screening Assessments

SARS-CoV-2 PCR testing, Chest CT or radiograph scans are performed to confirm SARS-CoV-2 infection and lung involvement and conducted as part of the participant's routine clinical management will be utilized for screening purposes, including those performed for initial assessment at hospitalization prior to screening period.

Laboratory testing performed for clinical management may be used for screening assessment if obtained within 3 days of planned randomization.

EKG performed for clinical management may be used for screening assessment if obtained within 7 days of planned randomization.

Efficacy Assessments

Assessments performed to evaluate efficacy include the following:

Blood Biomarkers of Efficacy

NETosis

-   -   cell-free DNA     -   citrullinated histone H3     -   Myeloperoxidase (MPO)-DNA complexes)

Neutrophil Elastase

-   -   Plasma desmosine/isodesmosine

Inflammation

-   -   Absolute and percentage neutrophil count     -   Absolute and percentage lymphocyte count     -   Neutrophil-lymphocyte ratio [NLR] derived     -   C-Reactive protein     -   IL-1 beta     -   IL-6     -   IL-8     -   TNF-alpha)     -   Procalcitonin

Coagulopathy

-   -   D-dimer

In addition, samples will be stored and analysis may be performed on additional biomarker variants thought to play a role in neutrophil elastase-induced damage to evaluate their association with observed neutrophil activation responses to alvelestat.

SaO₂/FiO₂ (Oxygen Saturation/Fraction Inspired Oxygen

The ratio of O₂ saturation to fraction inspired O₂ (SaO₂/FiO₂) is a reliable, non-invasive surrogate for PaO2/FiO2 and predictive for 3-day worsening in patients with COVID-19 infection ([20]). This will be collected at baseline and during the study, measured as per local standard operating procedures.

WHO 9-Point Ordinal Scale

Each assessment will be recorded as a number based on the status categories below. Where possible the timing of each assessment should be similar (i.e. morning or evening throughout)

-   -   0. Uninfected, no clinical or virological evidence of infection     -   1. Ambulatory, no limitation of activities     -   2. Ambulatory, limitation of activities     -   3. Hospitalized—mild disease, no oxygen therapy     -   4. Hospitalized—mild disease, oxygen by mask or nasal prongs     -   5. Hospitalized—severe disease, noninvasive ventilation or high         flow oxygen     -   6. Hospitalized—severe disease, intubation and mechanical         ventilation     -   7. Hospitalized—severe disease, ventilation and additional organ         support—vasopressors, renal replacement therapy, extracorporeal         membrane oxygenation     -   8. Death

Safety Assessments

Assessments performed to evaluate safety include the following:

Physical Examinations

-   -   A complete physical examination will include, at a minimum,         assessments of the cardiovascular, respiratory,         gastrointestinal, integumentary, and neurological systems.         Height and weight will also be measured and recorded.     -   A brief physical examination will include, at a minimum,         assessments of the lungs, heart, abdomen, and skin.     -   Investigators should pay special attention to clinical signs         related to COVID-19 disease.

Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include temperature, systolic and diastolic blood pressure, heart rate, respiratory rate, and pulse oximetry.

-   -   Oral or tympanic temperature.     -   Blood pressure and pulse measurements will be assessed with a         completely automated device. Manual techniques will be used only         if an automated device is not available.     -   Blood pressure and pulse measurements should be preceded by at         least 5 minutes of rest for the participant in a quiet setting         without distractions (e.g., television, cell phones).

Electrocardiograms

-   -   12-lead EKG will be obtained using an EKG machine that         automatically calculates the heart rate and measures PR, QRS,         QT, and QTc intervals where possible.     -   Single EKGs will be performed at all scheduled time points, with         the exception of when a change from baseline occurs that meets         drug discontinuation criteria. In this situation, a triplicate         measurement is required to confirm the finding and for         discontinuation decisions.     -   When a triplicate EKG is required, 3 consecutive EKG tracings         should be taken in a 30-minute period with at least 5 minutes         between each EKG.     -   QTc value will be calculated using the Fridericia formula         (QTc=QT/3√RR)

Schedule of Assessments Study period Screening Study Treatment Period (daily Period assessment for adverse events) Visit Name Baseline/ Dose Dose Screening Randomize Escalation 1 Escalation 2 Study Day Day −2 to Day −1 (screening and randomization can be on same day) Day 1 Day 2 Day 3 Eligibility check X Informed consent X Medical History X Randomization X Physical exam (full at screening, X X X X limited thereafter) Study Drug dosing X (120 mg bid) X (180 mg bid) X (240 mg bid) Interim history concomitant med X X X X and adve

 vent recording¹ Pregnan

 t (high sensitivity X X serum

 screening, urine thereafte

Chest Ra

 raphy or CT² X Blood draw (screening and in- X X X study safety monitoring)² Blood draw (biomarkers) X SaO2/FiO2 X Blood (PK)³ X EKG^(2, 4) X X WHO ordinal scale assessment X Study period Study Treatment Period (daily assessment for adverse events) Follow Up Period Visit Name Final Safety Safety End of Safety Outcome Follow Up Follow Up Treatment Follow Up Assessment (FU) 1 (FU) 2 (EoT) (FU) 3 (FOA) Study Day Day 14 (+/−1 day) Day 10 or 4 Day 7 or EoT (+/−1) days Day 29 Day 4 (+/−1 day) (+/−1 day) after EoT (+/−2 days) Eligibility check Informed consent Medical History Randomization Physical exam (full at screening, X X X X limited thereafter) Study Drug dosing X (240 mg bid) Interim history concomitant med X X X X X and adve

 vent recording¹ Pregnan

 t (high sensitivity X serum

 screening, urine thereafte

Chest Ra

 raphy or CT² Blood draw (screening and in-  X⁶ X X X study safety monitoring)² Blood draw (biomarkers) X X SaO2/FiO2 X Blood (PK)³ X EKG^(2, 4) X WHO ordinal scale assessment X X  X⁵ ¹Only SAEs to be collected prior to randomization ²Investigations performed as part of routine clinical assessment of COVID-19 may be used for eligibility ³Time of PK and last dose of study medication to be recorded in CRF ⁴EKG to be taken 1-2 hours after study drug dosing when feasible ⁵Telehealth visit if hospital discharge occurs before Day 29 ⁶May also be taken on Day 5 to align with clinical management sampling

indicates data missing or illegible when filed

REFERENCES

-   [1] Grein, J., Ohmagari, N., Shin, D. et al. (2020). Compassionate     Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med,     382(24), 2327-2336. doi: 10.1056/nejmoa2007016 -   [2] Cao, B., Wang, Y., Wen, D. et al. (2020). A Trial of     Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N     Engl J Med, 382(19), 1787-1799. doi: 10.1056/nejmoa2001282 -   [3] Geleris, J., Sun, Y., Platt, J. et al. (2020). Observational     Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.     N Engl J Med, 382(25), 2411-2418. doi: 10.1056/nejmoa2012410 -   [4] Ingraham, N. E., Lotfi-Emran, S., Thielen, B. K. et al. (2020).     Immunomodulation in COVID-19. Lancet Respir Med, 8(6), 544-546. doi:     10.1016/s2213-2600(20)30226-5 -   [5] Mercuro, N.J., Yen, C. F., Shim, D. J. et al. (2020). Risk of QT     Interval Prolongation Associated With Use of Hydroxychloroquine With     or Without Concomitant Azithromycin Among Hospitalized Patients     Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA     Cardiol. doi: 10.1001/jamacardio.2020.1834 -   [6] Papayannopoulos, V., Metzler, K. D., Hakkim, A. et al. (2010).     Neutrophil elastase and myeloperoxidase regulate the formation of     neutrophil extracellular traps. J Cell Biol, 191(3), 677-691. doi:     10.1083/jcb.201006052 -   [7] Kim, E. H., Wong, S-W., & Martinez, J. (2018). Programmed     Necrosis and Disease: We interrupt your regular programming to bring     you necroinflammation [sic]. Cell Death Differ, 26(1), 25-40. doi:     10.1038/s41418-018-0179-3 -   [8] McElvaney, O. J, McEvoy, N., McElvaney O. F. et al. (2020).     Characterization of the Inflammatory Response to Severe COVID-19     Illness. AJRCCM Published June 25. doi: 10.1164/rccm.202005-1583OC -   [9] Groutas W C, Dou D, Alliston K R, Expert Opin Ther Pat. 2011     March; 21(3): 339-354 -   [10] Mozzini 2020 -   [11] Stevens T, Ekholm K, Granse M, Lindahl M, Kozma V, Jungar C,     Ottosson T, Falk-Hakansson H, Churg A, Wright J L, Lal H,     Sanfridson A. AZD9668: pharmacological characterization of a novel     oral inhibitor of neutrophil elastase. The Journal of pharmacology     and experimental therapeutics. 2011; 339(1):313-20. Epub 2011/07/28.     doi: 10.1124/jpet.111.182139. PubMed PMID: 21791628. -   [12] Zuo, Y., Yalavarthi, S., Shi, H. et al. (2020). Neutrophil     extracellular traps in COVID-19. JCI Insight. 5(11), e138999. doi:     10.1172/jci. insight.138999 -   [13] Barnes, B. J., Adrover, J. M., Baxter-Stoltzfus, A. et al.     (2020). Targeting potential drivers of COVID-19: Neutrophil     extracellular traps. J Exp Med, 217(6). doi: 10.1084/jem.20200652 -   [14] Narasarju et al 2020 -   [15] Elborn, J. S., Perrett, J., Forsman-Semb, K. et al. (2012).     Efficacy, safety and effect on biomarkers of AZD9668 in cystic     fibrosis. Eur Respir J, 40(4), 969-976. doi:     10.1183/09031936.00194611 -   [16] Stockley, R., De Soyza, A., Gunawardena, K., Perrett, J.,     Forsman-Semb, K., Entwistle, N., & Snell, N. (2013). Phase II study     of a neutrophil elastase inhibitor (AZD9668) in patients with     bronchiectasis. Respir Med, 107(4), 524-533. doi:     10.1016/j.rmed.2012.12.009 -   [17] Li, H., Zhou, X., Tan, H. et al. (2018). Neutrophil     extracellular traps contribute to the pathogenesis of     acid-aspiration-induced ALI/ARDS. Oncotarget 9(2), 1772-1784. doi:     10.18632/oncotarget.22744 Argenziano et al 2020 -   [18] Vultaggio, A., Vivarelli E., Virgili, G, et al (2020). Prompt     predicting of early clinical deterioration of moderate-to-severe     COVID-19 patients: usefulness of a combined score using IL-6 in a     preliminary study (Pre-Proof) The Journal of Allergy and Clinical     Immunology: In Practice. June doi: 10.1016/j.jaip.2020.06.013 -   [19] Horby et al. Dexamethasone in Hospitalized Patients with     Covid-19—Preliminary Report The New England Journal of Medicine;     DOI: 10.1056/NEJMoa2021436 -   [20] Alain R. Thierry: Anti-Protease Treatments Targeting Plasmin     (Ogen) And Neutrophil Elastase May Be Beneficial In Fighting     COVID-19; Physiol Rev 100: 1597-1598, 2020,     doi:10.1152/physrev.00019.2020

The invention provides the following numbered embodiments:

-   1. A method for treating a coronavirus infection and/or preventing     progression of a coronavirus disease, comprising administering an     effective amount of alvelestat or a pharmaceutically acceptable salt     and/or solvate thereof to a subject in need thereof. -   2. A method for treating or preventing a symptom or complication of     a coronavirus infection, comprising administering an effective     amount of alvelestat or a pharmaceutically acceptable salt and/or     solvate thereof to a subject in need thereof. -   3. A method for reducing viral replication of coronavirus,     comprising administering alvelestat or a pharmaceutically acceptable     salt and/or solvate thereof, to a subject in need thereof. -   4. A method for treating or preventing a lung or respiratory     condition in a subject having a coronavirus infection, comprising     administering an effective amount of alvelestat or a     pharmaceutically acceptable salt and/or solvate thereof to the     subject. -   5. The method of any preceding embodiment, wherein the coronavirus     is severe acute respiratory syndrome coronavirus (SARS-CoV) or     Middle East respiratory syndrome coronavirus (MERS-CoV). -   6. The method of any of embodiments 1-5, wherein the coronavirus is     SARS-CoV. -   7. The method of embodiment 6, wherein the SARS-CoV is SARS-CoV-1 or     SARS-CoV-2. -   8. The method of any preceding embodiment, wherein the coronavirus     is SARS-CoV-2 (COVID-19). -   9. A method for treating and/or preventing progression of COVID-19,     comprising administering an effective amount of alvelestat or a     pharmaceutically acceptable salt and/or solvate thereof to a subject     in need thereof. -   10. A method for reducing viral replication of COVID-19, comprising     administering an effective amount of alvelestat or a     pharmaceutically acceptable salt and/or solvate thereof to a subject     in need thereof. -   11. A method for treating or preventing a symptom or complication of     COVID-19, comprising administering an effective amount of alvelestat     or a pharmaceutically acceptable salt and/or solvate thereof to a     subject in need thereof. -   12. The method of any preceding embodiment, comprising the treatment     or prevention of one or more symptom, complication or condition     selected from the group consisting of: a disease with signs and/or     symptoms similar to Kawasaki disease, acute respiratory distress     syndrome (ARDS), ageusia, arrhythmias, ALI, ALI/ARDS accompanied by     Disseminated intravascular coagulation (DIC), ALI/ARDS accompanied     by Systemic Inflammatory Response Syndrome, alveolar-capillary     damage, alveolitis, anosmia, APS, arterial thrombosis, blood clot,     bronchiectasis, cardiac complications, cardiovascular complications,     chest tightness, coagulopathy, coagulopathy and/or excessive     bleeding, coagulopathy complications, coughing, coughing up sputum,     cystic fibrosis, cytokine release syndrome, cytokine storm     hyperinflammation, cytokine storm syndrome, DIC and/or excessive     bleeding, Dyspnea, Encephalitis, Encephalopathy, excessive bleeding,     fatigue, fever, Guillain-Barré syndrome, heart failure, heart     inflammation, heart palpitations, hyperinflammation, hypoxemia,     inflammation disorders, inflammation disorders in paediatric     subjects, inflammation of the lungs, Kawasaki disease, loss of     appetite, loss of smell, loss of taste, lung consolidation,     microthrombosis, multi-organ failure, muscle ache, neurological     complications, neurological disorders, neutrophilia, Paediatric     Inflammatory Multisystem Syndrome Temporally associated with     SARS-CoV-2 (PIMS-TS), Pericarditis, Pleurisy, Pneumonia, pulmonary     disease, pulmonary embolism, pulmonary fibrosis, pulmonary oedema,     renal complications, renal failure, respiratory failure, seizure,     septic shock, shock, shortness of breath, stroke, Systemic     inflammatory response syndrome (SIRS), Thromboses, thromboses and/or     excessive bleeding, thrombosis or thromboses including venous and     arterial thrombosis, thrombotic complications, vascular catheter     thrombosis, vasculitis, vasculopathy, venous thrombosis, and viral     pneumonia. -   13. The method of any preceding embodiment, comprising the treatment     or prevention of ALI. -   14. The method of any preceding embodiment, comprising the treatment     or prevention of ARDS. -   15. The method of any preceding embodiment, comprising the treatment     or prevention of APS. -   16. The method of any preceding embodiment, comprising the treatment     or prevention of respiratory failure. -   17. The method of any preceding embodiment, comprising the treatment     or prevention of organ failure. -   18. The method of any preceding embodiment, comprising the treatment     or prevention of a coagulopathy complication. -   19. The method of any preceding embodiment, comprising the treatment     or prevention of inflammation. -   20. The method of any preceding embodiment, comprising treating or     preventing neutrophilia. -   21. The method of any preceding embodiment, comprising treating or     preventing coagulopathy (e.g. one or more of disseminated     intravascular coagulation, thromboses and/or excessive bleeding). -   22. A method for treating or preventing ALI in a subject with a     coronavirus infection, in particular SARS-COV (e.g. COVID-19),     comprising administering an effective amount of alvelestat or a     pharmaceutically acceptable salt and/or solvate thereof to a subject     in need thereof. -   23. A method for treating or preventing ARDS in a subject with a     coronavirus infection, in particular SARS-COV (e.g. COVID-19),     comprising administering an effective amount of alvelestat or a     pharmaceutically acceptable salt and/or solvate thereof to a subject     in need thereof. -   24. A method for treating or preventing neutrophilia in a subject     with a coronavirus infection, in particular SARS-COV (e.g.     COVID-19), comprising administering an effective amount of     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof to a subject in need thereof. -   25. A method for treating or preventing coagulopathy (e.g. one or     more of disseminated intravascular coagulation, thromboses and/or     excessive bleeding) in a subject with a coronavirus infection, in     particular SARS-COV (e.g. COVID-19), comprising administering an     effective amount of alvelestat or a pharmaceutically acceptable salt     and/or solvate thereof to a subject in need thereof. -   26. A method for treating or preventing respiratory failure in a     subject with a coronavirus infection, in particular SARS-COV (e.g.     COVID-19), comprising administering an effective amount of     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof to a subject in need thereof. -   27. A method for treating or preventing inflammation in a subject     with a coronavirus infection, in particular SARS-COV (e.g.     COVID-19), comprising administering an effective amount of     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof to a subject in need thereof. -   28. A method for treating or preventing lung injury in a subject     with a coronavirus infection, in particular SARS-COV (e.g.     COVID-19), comprising administering an effective amount of     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof to a subject in need thereof. -   29. A method for treating or preventing thrombosis in a subject with     a coronavirus infection, in particular SARS-COV (e.g. COVID-19),     comprising administering an effective amount of alvelestat or a     pharmaceutically acceptable salt and/or solvate thereof to a subject     in need thereof. -   30. A method for treating or preventing thrombosis in a subject with     organ failure, in particular SARS-COV (e.g. COVID-19), comprising     administering an effective amount of alvelestat or a     pharmaceutically acceptable salt and/or solvate thereof to a subject     in need thereof. -   31. The method of any preceding embodiment, wherein the subject also     suffers from a disease selected from obesity, hypertension, and     diabetes (e.g. type 2 diabetes). -   32. The method of any preceding embodiment, wherein the subject     requires hospitalisation. -   33. The method of any preceding embodiment, wherein the subject has     pulmonary disease. -   34. The method of any preceding embodiment, wherein the subject has     evidence of pulmonary disease on an imaging method, optionally     wherein the imaging method is a chest radiograph and/or Computerised     Tomography (CT). -   35. The method of any preceding embodiment, wherein the subject does     not require ventilation. -   36. The method of any of embodiments 1-34, wherein the subject     requires ventilation, optionally wherein the ventilation is     mechanical ventilation. -   37. The method of any preceding embodiment, wherein the subject does     not require intubation. -   38. The method of any of embodiments 1-36, wherein the subject     requires intubation. -   39. The method of any preceding embodiment, wherein the subject does     not have multi-organ failure. -   40. The method of any preceding embodiment, wherein the subject has     a score of Grade 3 to 5 on the WHO 9-point Ordinal Scale. -   41. The method of any preceding embodiment comprising inhibiting     neutrophil elastase. -   42. The method of any preceding embodiment, comprising reducing     neutrophil elastase activity. -   43. The method of any preceding embodiment, wherein the subject has     elevated neutrophil elastase activity. -   44. The method of any preceding embodiment, wherein the subject has     elevated levels of NETosis. -   45. The method of any preceding embodiment, wherein the subject has     elevated levels of NETs. -   46. The method of any preceding embodiment, wherein the subject has     inflammation, optionally lung inflammation. -   47. The method of any preceding embodiment, wherein the subject has     an acute innate inflammatory response. -   48. The method of the preceding embodiment, wherein the acute innate     inflammatory response comprises one or more of elevated     pro-inflammatory cytokines, elevation of acute phase reactants     and/or cytokine storm. -   49. The method of any preceding embodiment, wherein the subject has     elevated inflammation. -   50. The method of embodiments 41-42, wherein neutrophil elastase     inhibition or change in neutrophil elastase activity is determined     by one or more blood biomarkers. -   51. The method of any of embodiments 43-49 wherein the elevated     levels, activity and/or inflammation is determined by one or more     blood biomarkers in the subject. -   52. The method of any of embodiments 50-51, wherein the one or more     blood biomarker are plasma desmosine, isodesmosine, and/or     A-alpha-Val. -   53. The method of embodiments 50-51, wherein the one or more blood     biomarkers are selected from the group consisting of cell-free DNA,     citrullinated histone H3, Myeloperoxidase (MPO), Myeloperoxidase     (MPO)-DNA complexes, and/or Proteinase-3. -   54. The method of embodiments 50-51, wherein in the one or more     blood biomarkers are selected from the group consisting of absolute     and/or percentage neutrophil count, absolute and/or percentage     lymphocyte count, neutrophil-lymphocyte ratio [NLR], Erythrocyte     Sedimentation Rate (ESR), C-Reactive protein, fibrinogen, complement     components (e.g. C2, C4, C3, C5), Total Hemolytic complement,     complement breakdown products (e.g. C3a, C3b, C4a, C4b),     procalcitonin, pro-inflammatory cytokines (e.g. selected from     IL-1beta, IL-6, IL-8, and TNF-alpha), and D-Dimer. -   55. The method of embodiment 54, wherein the one or more blood     biomarkers are measured by markers of inflammation. -   56. The method of embodiment 55, wherein the markers of inflammation     are selected from proinflammatory cytokines (e.g. selected from IL-1     beta, IL-6, IL-8 and TNF-alpha) and coagulopathy (e.g. selected from     d-dimer prothrombin, thrombin, plasmin, P-selectin, clotting and     bleeding times, von Willebrand Factor, and/or platelet count). -   57. The method of any proceeding embodiment, wherein the marker is     d-dimer. -   58. The method of any preceding embodiment, comprising reducing the     formation of neutrophil extracellular traps (NETs) in the subject. -   59. The method of any preceding embodiment wherein the reduction in     the formation of neutrophil extracellular traps (NETs) is     characterised by a reduction in the levels of one or more blood     biomarkers of NETosis. -   60. The method of the preceding embodiment, wherein the one or more     blood biomarkers are selected from the group consisting of cell-free     DNA, citrullinated histone H3, Myeloperoxidase (MPO),     Myeloperoxidase (MPO)-DNA complexes. -   61. The method of any preceding embodiment, comprising reducing     NETosis in the subject. -   62. The method of any preceding embodiment, comprising reducing     inflammation in the subject. -   63. The method of the preceding embodiment, wherein the reduction in     inflammation is characterised by a reduction in the levels of one or     more blood biomarkers of inflammation. -   64. The method of the preceding embodiment, wherein in the one or     more blood biomarkers are selected from the group consisting of     absolute and/or percentage neutrophil count, absolute and/or     percentage lymphocyte count, neutrophil-lymphocyte ratio [NLR],     Erythrocyte Sedimentation Rate (ESR), C-Reactive protein,     fibrinogen, complement components (e.g. C2, C4, C3, C5), Total     Hemolytic complement, complement breakdown products (e.g. C3a, C3b,     C4a, C4b), procalcitonin, pro-inflammatory cytokines (e.g. selected     from IL-1beta, IL-6, IL-8, and TNF-alpha), D-Dimer, prothrombin,     thrombin, plasmin, P-selectin, clotting and bleeding times, von     Willebrand Factor, and/or platelet count. -   65. The method of any preceding embodiment, wherein the inhibition     of neutrophil elastase or the reduction in the formation of NETs is     measured by markers of inflammation. -   66. The method of the preceding embodiment, wherein the markers of     inflammation are selected from proinflammatory cytokines (e.g.     selected from IL-1 beta, IL-6, IL-8 and TNF-alpha) and coagulopathy     (e.g. selected from d-dimer, prothrombin, thrombin, plasmin,     P-selectin, clotting and bleeding times, von Willebrand Factor,     and/or platelet count). -   67. The method of any preceding embodiment, comprising reducing the     levels of one or more biomarkers in the subject selected from the     group consisting of cell-free DNA, citrullinated histone H3,     Myeloperoxidase (MPO), Myeloperoxidase (MPO)-DNA complexes,     Proteinase-3, absolute and/or percentage neutrophil count, absolute     and/or percentage lymphocyte count, neutrophil-lymphocyte ratio     [NLR], Erythrocyte Sedimentation Rate (ESR), C-Reactive protein,     fibrinogen, complement components (e.g. C2, C4, C3, C5), Total     Hemolytic complement, complement breakdown products (e.g. C3a, C3b,     C4a, C4b), procalcitonin, pro-inflammatory cytokines (e.g. selected     from IL-1beta, IL-6, IL-8, and TNF-alpha), D-Dimer, prothrombin,     thrombin, plasmin, P-selectin, clotting and bleeding times, von     Willebrand Factor, platelet count, desmosine, isodesmosine, and/or     A-alpha-Val. -   68. The method of any preceding embodiment, wherein following     treatment or during treatment, the subject has a decrease in the     levels of one or more biomarkers of elastase activity. -   69. The method of any preceding embodiment, wherein following     treatment or during treatment, the subject has a decrease in the     levels of one or more biomarkers, optionally the pro-inflammatory     biomarkers Interleukin (IL)-6. -   70. The method of any preceding embodiment, comprising improving or     preventing worsening of SaO₂/FiO₂ (the ratio of O₂ saturation to     fraction inspired O₂) in the subject. -   71. The method of any preceding embodiment, comprising improving or     preventing worsening of SaO2/FiO₂, PaO₂/FiO₂ or SpO₂. -   72. The method of the preceding embodiment, wherein the SaO₂/FiO₂ is     increased in the subject. -   73. The method of any preceding embodiment, wherein SaO₂/FiO₂ in the     subject is less than about 300. -   74. The method of any preceding embodiment, wherein SaO₂/FiO₂ in the     subject is about 300 to about 200. -   75. The method of any preceding embodiment, wherein SaO₂/FiO₂ in the     subject is about 200 to about 100. -   76. The method of any preceding embodiment, wherein SaO₂/FiO₂ in the     subject is about 100 to about 200. -   77. The method of any preceding embodiment, wherein SaO₂/FiO₂ in the     subject is about 200 to about 300. -   78. The method of any preceding embodiment, wherein SaO₂/FiO₂ in the     subject is greater than about 300. -   79. The method of any preceding embodiment comprising improving or     preventing worsening of SpO₂ (peripheral oxygen saturation) in the     subject. -   80. The method of the preceding embodiment, wherein SpO₂ is measured     by a pulse oximeter. -   81. The method of embodiment 79 or 80, wherein SpO₂ is less than or     equal to 95% before treatment. -   82. The method of any preceding embodiment, comprising improving or     preventing worsening of forced expiratory volume in 1 second (FEV1)     in the subject. -   83. The method of any preceding embodiment, comprising improving or     preventing worsening of the condition of the subject according to     the WHO 9-point ordinal scale. -   84. The method of any preceding embodiment, comprising improving the     condition of the subject according to the WHO 9-point ordinal scale. -   85. The method of any preceding embodiment, comprising improving the     condition of the subject by at least 1 point according to the WHO     9-point ordinal scale. -   86. The method of any preceding embodiment, comprising improving the     condition of the subject by at least 2 points according to the WHO     9-point ordinal scale. -   87. The method of any preceding embodiment wherein alvelestat is in     the form of the free base. -   88. The method of any preceding embodiment wherein alvelestat is in     the form of alvelestat tosylate. -   89. The method of any preceding embodiment comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof in a tablet. -   90. The method of any preceding embodiment comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof twice daily. -   91. The method of any preceding embodiment comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof at a dose of alvelestat of up to 240 mg twice daily. -   92. The method of any preceding embodiment comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof at a dose of alvelestat of 60 mg, 120 mg, 180 mg or 240 mg     twice daily. -   93. The method of any preceding embodiment comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof at a dose of alvelestat of 240 mg twice daily. -   94. The method of any preceding embodiment, comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof for 10 days. -   95. The method of any preceding embodiment, comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof at a dose of alvelestat of 120 mg bid on day 1, 180 mg bid     on day 2, and 240 mg bid on days 3-10. -   96. The method of any preceding embodiment, wherein the twice daily     doses are given about 12 hours apart. -   97. The method of any preceding embodiment, wherein the daily     dose(s) results in a plasma concentration of alvelestat of greater     than or equal to 300 nM. -   98. The method of any preceding embodiment comprising administering     alvelestat or a pharmaceutically acceptable salt and/or solvate     thereof by oral administration. -   99. The method of any preceding embodiment, further comprising     administering to the subject one or more additional therapeutic     agents. -   100. The method of embodiment 99, wherein the one or more additional     therapeutic agents is selected from remdesivir, nitric oxide,     lopinavir and ritonavir, favipiravir, atlizumab, angiotensin II,     interferon (e.g. inhaled interferon), dexamethasone and     hydroxychloroquine. -   101. The method of embodiment 91, wherein the one or more additional     therapeutic agents is selected from an antiviral agent, an     anti-inflammatory agent, an analgesic agent, a steroid, an antibody,     a vaccine, an antimalarial agent, and an enzymatic agent. -   102. The method of embodiment 101, wherein the vaccine is selected     from the group consisting of VPM1002, MMR vaccine. ChAdOx1 nCoV-19,     BCG vaccine, PrEP-001, mRNA-1273, CoronaVac, Ad5-nCoV, a     coronavirus-based vaccine, V-SARS, NVX-CoV2372, Inactivated     SARS-CoV-2 Vaccine, GX-19, BNT162 mRNA vaccine, AV-COVID-19, ZyCoVD,     S-protein vaccine, RUTI vaccine, aAPC vaccine, LNP-nCoVsaRNA,     INO-4800 DNA vaccine, CVnCoV vaccine, bacTRL-Spike, TNX-1800, and     anti-SARS-CoV-2 convalescent plasma, and combinations thereof. -   103. The method of embodiment 101, wherein the one or more     additional therapeutic agents is an antiviral agent. -   104. The method of embodiment 103 wherein the antiviral agent is     selected from the group consisting of Abacavir, Acyclovir     (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase),     Arbidol Umifenovir, Atazanavir, Atripla, Baloxavir marboxil     (Xofluza), Biktarvy, Boceprevir, Cidofovir, Cobicistat (Tybost),     Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy,     Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro),     Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide,     Entecavir, Etravirine (Intelence), Famciclovir, Favilavir,     Fomivirsen, Fosamprenavir, Foscarnet, Ganciclovir (Cytovene),     Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod,     Imunovir, Indinavir, Lamivudine, Letermovir (Prevymis), Lopinavir,     Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir,     Nevirapine, Nexavir formerly (Kutapressin), Nitazoxanide, Norvir,     Oseltamivir, OYA1, Penciclovir, Peramivir, Penciclovir, Peramivir     (Rapivab), Pleconaril, Podophyllotoxin, Raltegravir, Remdesivir,     Ribavirin, Rilpivirine (Edurant), Rilpivirine, Rimantadine,     Ritonavir, Saquinavir, Simeprevir (Olysio), Sofosbuvir, Stavudine,     Taribavirin (Viramidine), Telaprevir, Telbivudine (Tyzeka),     Tenofovir alafenamide, Tenofovir disoproxil, Tenofovir, Tipranavir,     Trifluridine, Trizivir, Tromantadine, Truvada, Umifenovir,     Valaciclovir, Valganciclovir (Valtrex), Vicriviroc, Vidarabine,     Zalcitabine, Zanamivir (Relenza), Zidovudine, umifenovir, danoprevir     and ritonavir, carrimycin, camostat, baloxavir marboxil,     azithromycin, triazayirin, oseltamivir, nitazoxanide, famotidine,     emtricitabine and tenofovir disoproxil fumarate, Convalescent     Plasma, ASC09 and ritonavir, VERU-111, selinexor, PP-001,     piclidenoson, merimepodib, ionafarnib, IMU-838, hyperimmune plasma,     galidesivir, FW-1022, Niclosamide, FP-025, fluidase, elsulfavirine,     EIDD-2801, clevudine, bemcentinib, azvudine, ATR-002, AQCH, aplidin,     LY-CoV555, NKG2D-ACE2 CAR-NK Cells, meplazumab, CYNK-001, brequinar,     TY027, NK cells, mefuparib, leflunomide, JS016, FT516, COVID-HIG,     and BC007, and combinations thereof. -   105. The method of embodiment 99 wherein the one or more therapeutic     agents is selected from the group consisting of immunotherapy with     anti-COVID-19 antibodies, BPI-002, Ifenprodil, Brilacidin,     Duvelisib, Tramadol, C21, Deferoxamine, Azithromycin,     Methylprednisolone, Chlorpromazine, Enoxaparin, DAS181,     Isotretinoin, Sirolimus, Lactoferrin, Clopidogrel, Rivaroxaba,     Clevudine, MCN (Methylene blue, vitamin C, N-acetyl cysteine),     Pegylated interferon lambda, CPI-006, epoprostenol, Recombinant     Bacterial ACE2 receptors, Recombinant Human ACE2, heparin,     Fondapariniux, Argatroban, TXA127, AG0301-COVID19, Baricitinib, 13     cis retinoic acid, All trans retinoic acid, ABX464, Clazakizumab,     IFX-1, camostat mesilate, mavrilimumab, Pamrevlumab,     Povidone-iodine, Zanubrutinib, Famotidine, Nitazoxanide and     atazanavir/ritonavir, Losartan, Ivermectin, Dapagliflozin,     REGN10933+REGN10987, Recombinant human angiotensin-converting enzyme     2 (rhACE2), Bemiparin, Ozanimod, Naproxen, Intravenous Immune     Globulin, Plitidepsin, Colchicine, Interferon beta-1b, Clofazimine,     Ruxolitinib, NK cells, IL15-NK cells, NKG2D CAR-NK cells, ACE2     CAR-NK cells, NKG2D-ACE2 CAR-NK cells, Acalabrutinib, Sarilumab,     BDB-001, Nafamostat, Telmisartan, Thymalfasin, Interferon Beta-1A,     Bicalutamide, Ciclesonide, Doxycycline, Anakinra, Estradiol,     Prazosin, Pentoxifylline, Rivaroxaban, Umifenovir, MRx-4DP0004,     Crizanlizumab, Siltuximab, Tetrandrine, avdoralimab, Olokizumab,     lanadelumab, Pacritinib, Montelukast, Sargramostim, Apilimod,     Sildenafil, Zilucoplan, OP-101, Gimsilumab, TJM2 (a neutralising     antibody), TZLS-501 (a monoclonal antibody), leronlimab, Infliximab,     Tocilizumab, chloroquine, hydroxychloroquine, APN01, Dornase alfa,     dexamethasone, ibuprofen, paracetamol, aspirin, Bivalirudin, AT-001,     Probiorinse, SCB-2019, Amiodarone, Verapamil, Atorvastatin,     Angiotensin peptide (1-7) derived plasma, CAP-1002, Etoposide,     Tofacitinib, AVM0703, hydrocortisone, Tranexamic acid, Bromhexine,     Imatinib, Lenalidomide, N-Acetyl cysteine, Dipyridamole,     lactoferrin, Ravulizumab, Atovaquone, Simvastatin, PHR160,     Ulinastatin, Melatonin, RhACE2 APN01, XPro1595, AT-527, EDP1815,     Ambrisentan, Methotrexate, Degarelix, LY3819253, BAT2020, Quercetin,     N-803, STI-1499, RBT-9, Levilimab, Peginterferon Lambda-la,     Levamisole, Formoterol, Budesonide, Abivertinib, AV-COVID-19,     PUL-042, Defibrotide, Virazole, RTB101, co-trimoxazole, nangibotide,     RESP301, Vazegepant, IC14, Enzalutamide, Bevacizumab, Human     immunoglobulin, immunoglobulin, Fluvoxamine, DFV890, MSTT1041A,     Sofusbuvir, Camostat, LAU-7b, thalidomide, metenkefalin,     tridecactide, MAS825, SAB-185, Nivolumab, Sirukumab, MV130,     Indomethacin, Iloprost, Lenzilumab, TD-0903, ATYR1923, Silymarin,     Imitrine, Isoprinosine, Eculizumab, TJ003234, Fluoxetine, Octagam,     CD24Fc, Garadacimab, Dociparastat, NK-1R antagonist, CK0802,     Recombinant human plasma gelsolin (Rhu-pGSN), Diphenhydramine,     Oxytocin, ANG-3777, AMY-101, ACE inhibitors (ACEls), angiotensin     receptor blockers, LEAF-4L6715, LEAF-4L7520, Lucinactant, Opaganib,     poractant alfa, Ethyl eicosapentaenoic acid, Interleukin-7, SBI-101,     Pyridostigmine Bromide, Artemisinin, Artesunate, CYT107, BLD-2660,     Sevoflurane, IMM-101, GLS-1200, Prasugrel, HB-adMSCs, P2Et     (Caesalpinia spinosa extract), LB1148, Dexmedetomidine, TY027,     BMS-986253, PTC299, Hidroxicloroquina, CERC-002, captopril, DUR-928,     DeltaRex-G, Valsartan, ArtemiC, aviptadil, MK-5475, ASC09F,     Thiazidem, NA-831, Naltrexone, Ketamine, Nintedanib, Calcifediol,     Secukinumab, PB1046, T89, MenACWY, Leronlimab, azoximer bromide,     SNDX-6352, TL-895, Linagliptin, Alteplase, Ibudilast, Ibrutinib,     XAV-19, BNT162a1, BNT162b1, BNT162b2, BNT162c2, CM4620, CSTC-Exo,     Spironolactone, Conestat alfa, Tirofiban, Acetylsalicylic acid,     cholecalciferol, Plaquenil, SAR443122, Pertuzumab, Trastuzumab,     Tradipitant, and TAK-981, and combinations thereof. -   106. The method of embodiment 101, wherein the analgesic agent is     selected from the group consisting of acetaminophen, a Non-steroidal     anti-inflammatory drug (NSAIDs) (e.g. one or more of ibuprofen,     naproxen, and/or celecoxib), paracetamol, acetylsalicylic acid, and     codeine, and combinations thereof. -   107. The method of embodiment 101, wherein the one or more     additional therapeutic agents is a steroid agent. -   108. The method of embodiment 107, wherein the steroid agent is a     corticosteroid. -   109. The method of embodiment 108, wherein the corticosteroid is     selected from methylprednisolone, prednisone, prednisolone,     budesonide, and/or dexamethasone. -   110. The method of embodiment 101, wherein the one or more     additional therapeutic agents is an anti-TNF agent. -   111. The method of embodiment 110, wherein the anti-TNF agent is     selected from infliximab, etanercept, certolizumab, golimumab,     adalimumab, adalimumab, Thalidomide, lenalidomide, pomalidomide,     pentoxifylline, and/or bupropion. 

1. A method for treating a coronavirus infection and/or preventing progression of a coronavirus disease, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
 2. A method for treating or preventing a symptom or complication of a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
 3. A method for reducing viral replication of coronavirus, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
 4. A method for treating or preventing a lung or respiratory condition in a subject having a coronavirus infection, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
 5. The method of any preceding claim, wherein the coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV) or Middle East respiratory syndrome coronavirus (MERS-CoV).
 6. The method of any of claims 1-5, wherein the coronavirus is SARS-CoV, optionally, wherein the SARS-CoV is SARS-CoV-1 or SARS-CoV-2.
 7. The method of any preceding claim, wherein the coronavirus is SARS-CoV-2 (COVID-19).
 8. A method for treating and/or preventing progression of COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
 9. A method for reducing viral replication of COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
 10. A method for treating or preventing a symptom or complication of COVID-19, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
 11. The method of any preceding claim, comprising the treatment or prevention of one or more symptom, complication or condition selected from the group consisting of: a disease with signs and/or symptoms similar to Kawasaki disease, acute respiratory distress syndrome (ARDS), ageusia, arrhythmias, ALI, ALI/ARDS accompanied by Disseminated intravascular coagulation (DIC), ALI/ARDS accompanied by Systemic Inflammatory Response Syndrome, alveolar-capillary damage, alveolitis, anosmia, APS, arterial thrombosis, blood clot, bronchiectasis, cardiac complications, cardiovascular complications, chest tightness, coagulopathy, coagulopathy and/or excessive bleeding, coagulopathy complications, coughing, coughing up sputum, cystic fibrosis, cytokine release syndrome, cytokine storm hyperinflammation, cytokine storm syndrome, DIC and/or excessive bleeding, Dyspnea, Encephalitis, Encephalopathy, excessive bleeding, fatigue, fever, Guillain-Barré syndrome, heart failure, heart inflammation, heart palpitations, hyperinflammation, hypoxemia, inflammation disorders, inflammation disorders in paediatric subjects, inflammation of the lungs, Kawasaki disease, loss of appetite, loss of smell, loss of taste, lung consolidation, microthrombosis, multi-organ failure, muscle ache, neurological complications, neurological disorders, neutrophilia, Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS), Pericarditis, Pleurisy, Pneumonia, pulmonary disease, pulmonary embolism, pulmonary fibrosis, pulmonary oedema, renal complications, renal failure, respiratory failure, seizure, septic shock, shock, shortness of breath, stroke, Systemic inflammatory response syndrome (SIRS), Thromboses, thromboses and/or excessive bleeding, thrombosis or thromboses including venous and arterial thrombosis, thrombotic complications, vascular catheter thrombosis, vasculitis, vasculopathy, venous thrombosis, and viral pneumonia.
 12. The method of any preceding claim, comprising the treatment or prevention of ALI, ARDS, APS, respiratory failure, organ failure, a coagulopathy complication, inflammation, and/or neutrophilia.
 13. The method of any preceding claim, comprising treating or preventing coagulopathy (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding).
 14. A method for treating or preventing ALI, ARDS, neutrophilia, coagulopathy (e.g. one or more of disseminated intravascular coagulation, thromboses and/or excessive bleeding), respiratory failure, inflammation, lung injury, thrombosis, and/or thrombosis in a subject with organ failure, in particular SARS-COV (e.g. COVID-19), comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
 15. The method of any preceding claim, wherein the subject also suffers from a disease selected from obesity, hypertension, and diabetes (e.g. type 2 diabetes); and/or wherein the subject requires hospitalisation; and/or wherein the subject has pulmonary disease; and/or wherein the subject has evidence of pulmonary disease on an imaging method, optionally wherein the imaging method is a chest radiograph and/or Computerised Tomography (CT); and/or wherein: (i) the subject does not require ventilation, or (ii) the subject requires ventilation, optionally wherein the ventilation is mechanical ventilation; and/or wherein: (i) the subject does not require intubation, or (ii) the subject requires intubation; and/or wherein the subject does not have multi-organ failure; and/or wherein the subject has a score of Grade 3 to 5 on the WHO 9-point Ordinal Scale.
 16. The method of any preceding claim comprising inhibiting neutrophil elastase and/or reducing neutrophil elastase activity.
 17. The method of any preceding claim, wherein the subject has elevated neutrophil elastase activity; and/or wherein the subject has elevated levels of NETosis; and/or wherein the subject has elevated levels of NETs; and/or wherein the subject has inflammation, optionally lung inflammation; and/or wherein the subject has an acute innate inflammatory response; and/or wherein the acute innate inflammatory response comprises one or more of elevated pro-inflammatory cytokines, elevation of acute phase reactants and/or cytokine storm; and/or wherein the subject has elevated inflammation.
 18. The method of any preceding claim, comprising improving or preventing worsening of SaO₂/FiO₂ (the ratio of O₂ saturation to fraction inspired O₂) in the subject.
 19. The method of any preceding claim, comprising improving or preventing worsening of SaO₂/FiO₂, PaO₂/FiO₂ or SpO₂.
 20. The method of the preceding claim, wherein the SaO₂/FiO₂ is increased in the subject.
 21. The method of any preceding claim, wherein SaO₂/FiO₂ in the subject is less than about 300; for example wherein SaO₂/FiO₂ in the subject is about 300 to about 200; or wherein SaO₂/FiO₂ in the subject is about 200 to about
 100. 22. The method of any preceding claim, wherein SaO₂/FiO₂ in the subject is greater than about
 300. 23. The method of any preceding claim comprising improving or preventing worsening of SpO₂ (peripheral oxygen saturation) in the subject; and/or wherein SpO₂ is measured by a pulse oximeter, optionally wherein SpO₂ is less than or equal to 95% before treatment.
 24. The method of any preceding claim, comprising improving or preventing worsening of forced expiratory volume in 1 second (FEV1) in the subject.
 25. The method of any preceding claim, comprising improving or preventing worsening of the condition of the subject according to the WHO 9-point ordinal scale.
 26. The method of any preceding claim, comprising improving the condition of the subject according to the WHO 9-point ordinal scale; for example comprising improving the condition of the subject by at least 1 point according to the WHO 9-point ordinal scale, for example comprising improving the condition of the subject by at least 2 points according to the WHO 9-point ordinal scale.
 27. The method of any preceding claim wherein alvelestat is in the form of the free base.
 28. The method of any preceding claim wherein alvelestat is in the form of alvelestat tosylate.
 29. The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof in a tablet.
 30. The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof twice daily.
 31. The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof at a dose of alvelestat of up to 240 mg twice daily; for example at a dose of alvelestat of 60 mg, 120 mg, 180 mg or 240 mg twice daily, preferably 240 mg twice daily.
 32. The method of any preceding claim, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for 10 days.
 33. The method of any preceding claim, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof at a dose of alvelestat of 120 mg bid on day 1, 180 mg bid on day 2, and 240 mg bid on days 3-10.
 34. The method of any preceding claim, wherein the twice daily doses are given about 12 hours apart.
 35. The method of any preceding claim, wherein the daily dose(s) results in a plasma concentration of alvelestat of greater than or equal to 300 nM.
 36. The method of any preceding claim comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof by oral administration.
 37. The method of any preceding claim, further comprising administering to the subject one or more additional therapeutic agents.
 38. The method of claim 37, wherein the one or more additional therapeutic agents is selected from remdesivir, nitric oxide, lopinavir and ritonavir, favipiravir, atlizumab, angiotensin II, interferon (e.g. inhaled interferon), dexamethasone and hydroxychloroquine.
 39. The method of claim 37, wherein the one or more additional therapeutic agents is selected from an antiviral agent, an anti-inflammatory agent, an analgesic agent, a steroid, an antibody, a vaccine, an antimalarial agent, and an enzymatic agent; optionally: (i) wherein the vaccine is selected from the group consisting of VPM1002, MMR vaccine. ChAdOx1 nCoV-19, BCG vaccine, PrEP-001, mRNA-1273, CoronaVac, Ad5-nCoV, a coronavirus-based vaccine, V-SARS, NVX-CoV2372, Inactivated SARS-CoV-2 Vaccine, GX-19, BNT162 mRNA vaccine, AV-COVID-19, ZyCoVD, S-protein vaccine, RUTI vaccine, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA vaccine, CVnCoV vaccine, bacTRL-Spike, TNX-1800, and anti-SARS-CoV-2 convalescent plasma, and combinations thereof; or (ii) wherein the one or more additional therapeutic agents is an antiviral agent, for example wherein the antiviral agent is selected from the group consisting of Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Arbidol Umifenovir, Atazanavir, Atripla, Baloxavir marboxil (Xofluza), Biktarvy, Boceprevir, Cidofovir, Cobicistat (Tybost), Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Entecavir, Etravirine (Intelence), Famciclovir, Favilavir, Fomivirsen, Fosamprenavir, Foscarnet, Ganciclovir (Cytovene), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Imunovir, Indinavir, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir, Nevirapine, Nexavir formerly (Kutapressin), Nitazoxanide, Norvir, Oseltamivir, OYA1, Penciclovir, Peramivir, Penciclovir, Peramivir (Rapivab), Pleconaril, Podophyllotoxin, Raltegravir, Remdesivir, Ribavirin, Rilpivirine (Edurant), Rilpivirine, Rimantadine, Ritonavir, Saquinavir, Simeprevir (Olysio), Sofosbuvir, Stavudine, Taribavirin (Viramidine), Telaprevir, Telbivudine (Tyzeka), Tenofovir alafenamide, Tenofovir disoproxil, Tenofovir, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Umifenovir, Valaciclovir, Valganciclovir (Valtrex), Vicriviroc, Vidarabine, Zalcitabine, Zanamivir (Relenza), Zidovudine, umifenovir, danoprevir and ritonavir, carrimycin, camostat, baloxavir marboxil, azithromycin, triazayirin, oseltamivir, nitazoxanide, famotidine, emtricitabine and tenofovir disoproxil fumarate, Convalescent Plasma, ASC09 and ritonavir, VERU-111, selinexor, PP-001, piclidenoson, merimepodib, ionafarnib, IMU-838, hyperimmune plasma, galidesivir, FW-1022, Niclosamide, FP-025, fluidase, elsulfavirine, EIDD-2801, clevudine, bemcentinib, azvudine, ATR-002, AQCH, aplidin, LY-CoV555, NKG2D-ACE2 CAR-NK Cells, meplazumab, CYNK-001, brequinar, TY027, NK cells, mefuparib, leflunomide, JS016, FT516, COVID-HIG, and BC007, and combinations thereof; or (iii) wherein the analgesic agent is selected from the group consisting of acetaminophen, a Non-steroidal anti-inflammatory drug (NSAIDs) (e.g. one or more of ibuprofen, naproxen, and/or celecoxib), paracetamol, acetylsalicylic acid, and codeine, and combinations thereof; or (iv) wherein the one or more additional therapeutic agents is a steroid agent, optionally wherein the steroid agent is a corticosteroid, for example wherein the corticosteroid is selected from methylprednisolone, prednisone, prednisolone, budesonide, and/or dexamethasone.
 40. The method of claim 37, wherein the one or more additional therapeutic agents is an anti-TNF agent wherein the anti-TNF agent is selected from infliximab, etanercept, certolizumab, golimumab, adalimumab, adalimumab, Thalidomide, lenalidomide, pomalidomide, pentoxifylline, and/or bupropion.
 41. The method of claim 37 wherein the one or more therapeutic agents is selected from the group consisting of immunotherapy with anti-COVID-19 antibodies, BPI-002, Ifenprodil, Brilacidin, Duvelisib, Tramadol, C21, Deferoxamine, Azithromycin, Methylprednisolone, Chlorpromazine, Enoxaparin, DAS181, Isotretinoin, Sirolimus, Lactoferrin, Clopidogrel, Rivaroxaba, Clevudine, MCN (Methylene blue, vitamin C, N-acetyl cysteine), Pegylated interferon lambda, CPI-006, epoprostenol, Recombinant Bacterial ACE2 receptors, Recombinant Human ACE2, heparin, Fondapariniux, Argatroban, TXA127, AG0301-COVID19, Baricitinib, 13 cis retinoic acid, All trans retinoic acid, ABX464, Clazakizumab, IFX-1, camostat mesilate, mavrilimumab, Pamrevlumab, Povidone-iodine, Zanubrutinib, Famotidine, Nitazoxanide and atazanavir/ritonavir, Losartan, Ivermectin, Dapagliflozin, REGN10933+REGN1 0987, Recombinant human angiotensin-converting enzyme 2 (rhACE2), Bemiparin, Ozanimod, Naproxen, Intravenous Immune Globulin, Plitidepsin, Colchicine, Interferon beta-1b, Clofazimine, Ruxolitinib, NK cells, IL15-NK cells, NKG2D CAR-NK cells, ACE2 CAR-NK cells, NKG2D-ACE2 CAR-NK cells, Acalabrutinib, Sarilumab, BDB-001, Nafamostat, Telmisartan, Thymalfasin, Interferon Beta-1A, Bicalutamide, Ciclesonide, Doxycycline, Anakinra, Estradiol, Prazosin, Pentoxifylline, Rivaroxaban, Umifenovir, MRx-4DP0004, Crizanlizumab, Siltuximab, Tetrandrine, avdoralimab, Olokizumab, lanadelumab, Pacritinib, Montelukast, Sargramostim, Apilimod, Sildenafil, Zilucoplan, OP-101, Gimsilumab, TJM2 (a neutralising antibody), TZLS-501 (a monoclonal antibody), leronlimab, Infliximab, Tocilizumab, chloroquine, hydroxychloroquine, APN01, Dornase alfa, dexamethasone, ibuprofen, paracetamol, aspirin, Bivalirudin, AT-001, Probiorinse, SCB-2019, Amiodarone, Verapamil, Atorvastatin, Angiotensin peptide (1-7) derived plasma, CAP-1002, Etoposide, Tofacitinib, AVM0703, hydrocortisone, Tranexamic acid, Bromhexine, Imatinib, Lenalidomide, N-Acetyl cysteine, Dipyridamole, lactoferrin, Ravulizumab, Atovaquone, Simvastatin, PHR160, Ulinastatin, Melatonin, RhACE2 APN01, XPro1595, AT-527, EDP1815, Ambrisentan, Methotrexate, Degarelix, LY3819253, BAT2020, Quercetin, N-803, STI-1499, RBT-9, Levilimab, Peginterferon Lambda-la, Levamisole, Formoterol, Budesonide, Abivertinib, AV-COVID-19, PUL-042, Defibrotide, Virazole, RTB101, co-trimoxazole, nangibotide, RESP301, Vazegepant, IC14, Enzalutamide, Bevacizumab, Human immunoglobulin, immunoglobulin, Fluvoxamine, DFV890, MSTT1041A, Sofusbuvir, Camostat, LAU-7b, thalidomide, metenkefalin, tridecactide, MAS825, SAB-185, Nivolumab, Sirukumab, MV130, Indomethacin, Iloprost, Lenzilumab, TD-0903, ATYR1923, Silymarin, Imitrine, Isoprinosine, Eculizumab, TJ003234, Fluoxetine, Octagam, CD24Fc, Garadacimab, Dociparastat, NK-1R antagonist, CK0802, Recombinant human plasma gelsolin (Rhu-pGSN), Diphenhydramine, Oxytocin, ANG-3777, AMY-101, ACE inhibitors (ACEls), angiotensin receptor blockers, LEAF-4L6715, LEAF-4L7520, Lucinactant, Opaganib, poractant alfa, Ethyl eicosapentaenoic acid, Interleukin-7, SBI-101, Pyridostigmine Bromide, Artemisinin, Artesunate, CYT107, BLD-2660, Sevoflurane, IMM-101, GLS-1200, Prasugrel, HB-adMSCs, P2Et (Caesalpinia spinosa extract), LB1148, Dexmedetomidine, TY027, BMS-986253, PTC299, Hidroxicloroquina, CERC-002, captopril, DUR-928, DeltaRex-G, Valsartan, ArtemiC, aviptadil, MK-5475, ASC09F, Thiazidem, NA-831, Naltrexone, Ketamine, Nintedanib, Calcifediol, Secukinumab, PB1046, T89, MenACWY, Leronlimab, azoximer bromide, SNDX-6352, TL-895, Linagliptin, Alteplase, Ibudilast, Ibrutinib, XAV-19, BNT162a1, BNT162b1, BNT162b2, BNT162c2, CM4620, CSTC-Exo, Spironolactone, Conestat alfa, Tirofiban, Acetylsalicylic acid, cholecalciferol, Plaquenil, SAR443122, Pertuzumab, Trastuzumab, Tradipitant, and TAK-981, and combinations thereof. 